Patent Publication Number: US-2015065436-A1

Title: INHIBITING INTERACTION BETWEEN HIF-1ALPHA AND p300/CBP WITH HYDROGEN BOND SURROGATE-BASED HELICES

Description:
This application claims the benefit of U.S. Provisional Patent Application Ser. No. 61/873,322, filed Sep. 3, 2013, which is hereby incorporated by reference in its entirety. 
    
    
     This invention was made with U.S. Government support under Grant No. CHE-1161644 awarded by the U.S. National Science Foundation and Grant No. R01GM073943 awarded by the National Institutes of Health. The U.S. Government has certain rights in this invention. 
    
    
     FIELD OF THE INVENTION 
     This invention is directed generally to methods of inhibiting the interaction between HIF-1 and p300/CBP using artificially constrained peptides and peptidomimetics that substantially mimic helix αB of the C-terminal transactivation domain of HIF-1α. 
     BACKGROUND OF THE INVENTION 
     The Role of HIF-1α-Coactivator Interactions in Regulation of VEGF Transcription 
     The interaction between the cysteine-histidine rich 1 domain (“CH1”) of the coactivator protein p300 (or the homologous CREB binding protein, CBP) and the C-terminal transactivation domain (“C-TAD,” aa 786-826 of NCBI accession number NP 001521) of the hypoxia-inducible factor 1α (“HIF-1α”) (Freedman et al., “Structural Basis for Recruitment of CBP/p300 by Hypoxia-Inducible Factor-1 α,” Proc. Nat&#39;l Acad. Sci. USA  99:5367-72 (2002); Dames et al., “Structural Basis for Hif-1α/CBP Recognition in the Cellular Hypoxic Response,”  Proc. Nat&#39;l Acad. Sci. USA  99:5271-6 (2002)) mediates transactivation of hypoxia-Inducible genes (Hirota &amp; Semenza, “Regulation of Angiogenesis by Hypoxia-Inducible Factor 1 ,” Crit. Rev. Oncol. Hematol.  59:15-26 (2006); Semenza, “Targeting HIF-1 for Cancer Therapy,”  Nat. Rev. Cancer  3:721-32 (2003)). Hypoxia-inducible genes are important contributors in angiogenesis and cancer metastasis, as shown in  FIGS. 1A-C  (Orourke et al., “Identification of Hypoxically Inducible mRNAs in HeLa Cells Using Differential-Display PCR,”  Eu. J. Biochem.  241:403-10 (1996); Ivan et al., “HIFα Targeted for VHL-Mediated Destruction by Proline Hydroxylation: Implications for O 2  Sensing,”  Science  292:464-8 (2001)). Under normoxia, the α-subunit of HIF-1 is successively hydroxylated at proline residues 402 and 564 by proline hydroxylases (Ivan et al., “HIFα Targeted for VHL-Mediated Destruction by Proline Hydroxylation: Implications for O 2  Sensing,”  Science  292:464-8 (2001)), ubiquitinated, and then degraded by the ubiquitin-proteosome system, as shown in  FIG. 2 . This process, mediated by the von Hippel-Lindau tumor suppressor protein (Kaelin, “Molecular Basis of the VHL Hereditary Cancer Syndrome,”  Nat. Rev. Cancer  2:673-82 (2002)), is responsible for controlling levels of HIF-1α and, as a result, the transcriptional response to hypoxia (Maxwell et al., “The Tumour Suppressor Protein VHL Targets Hypoxia-Inducible Factors for Oxygen-Dependent Proteolysis,”  Nature  399:271-5 (1999)). Under hypoxic conditions, HIF-1α is no longer targeted for destruction and accumulates. Heterodimerization with its constitutively expressed binding partner, aryl hydrocarbon receptor nuclear translocator (“ARNT”) (Wood et al., “The Role of the Aryl Hydrocarbon Receptor Nuclear Translocator (ARNT) in Hypoxic Induction of Gene Expression,”  J. Biol. Chem.  271:15117-23 (1996)) results in binding to a cognate hypoxia response element (“HRE”) (Forsythe et al., “Activation of Vascular Endothelial Growth Factor Gene Transcription by Hypoxia-Inducible Factor 1 ,” Mol. Cell. Biol.  16:4604-13 (1996)). A third site of regulatory hydroxylation on asparagine 803 is also inhibited under hypoxic conditions (Lando et al., “FIH-1 Is an Asparaginyl Hydroxylase Enzyme That Regulates the Transcriptional Activity of Hypoxia-Inducible Factor,”  Genes  &amp;  Develop.  16:1466-71 (2002)), allowing recruitment of the p300/CBP coactivators, which trigger overexpression of hypoxia inducible genes, as shown in  FIG. 2 . Among these are genes encoding angiogenic peptides such as vascular endothelial growth factor (“VEGF”) and VEGF receptors VEGFR-1 (Flt-1) and VEGFR-2 (KDR/Flk-1), as well as proteins involved in altered energy metabolism, such as the glucose transporters GLUT1 and GLUT3, and hexokinases 1 and 2 (Forsythe et al., “Activation of Vascular Endothelial Growth Factor Gene Transcription by Hypoxia-Inducible Factor 1 ,” Mol. Cell. Biol.  16:4604-13 (1996); Okino et al., “Hypoxia-Inducible Mammalian Gene Expression Analyzed in Vivo at a TATA-Driven Promoter and at an Initiator-Driven Promoter,”  J. Biol. Chem . 273:23837-43 (1998)). 
     Epidithiodiketopiperazine Fungal Metabolites as Regulators of Hypoxia-Inducible Transcription 
     Because interaction of HIF-1α C-TAD with transcriptional coactivator p300/CBP is a point of significant amplification in transcriptional response, its disruption with designed protein ligands can be an effective means of suppressing aerobic glycolysis and angiogenesis (i.e., the formation of new blood vessels) in cancers (Hirota &amp; Semenza, “Regulation of Angiogenesis by Hypoxia-Inducible Factor 1 ,” Crit. Rev. Oncol. Hematol.  59:15-26 (2006); Rarnanathan et al., “Perturbational Profiling of a Cell-Line Model of Tumorigenesis by Using Metabolic Measurements,”  Proc. Nat&#39;l Acad. Sci. USA  102:5992-7 (2005); Underiner et al., “Development of Vascular Endothelial Growth Factor Receptor (VEGFR) Kinase Inhibitors as Anti-Angiogenic Agents in Cancer Therapy,”  Curr. Med. Chem.  11:731-45 (2004)). Although the contact surface of the HIF-1α C-TAD with p300/CBP is extensive (3393 Å 2 ), the inhibition of this protein-protein interaction may not require direct interference. Instead, the induction of a structural change to one of the binding partners (p300/CBP) may be sufficient to disrupt the complex (Kung et al., “Small Molecule Blockade of Transcriptional Coactivation of the Hypoxia-Inducible Factor Pathway,”  Cancer Cell  6:33-43 (2004)). 
     The present invention is directed to overcoming these and other deficiencies in the art. 
     SUMMARY OF THE INVENTION 
     A first aspect of the present invention relates to a peptidomimetic, wherein the peptidomimetic: 
     (i) mimics a helix having the formula X 1 —X 2 —X 2 —X 3 —X 2 —X 2 —X 1 —X 4 —X 5 , wherein each X 1  is any negatively charged residue, each X 2  is any hydrophobic residue, X 3  is any positively-charged residue, X 4  is any polar residue, and X 5  is absent or any hydrophobic residue; and
 
(ii) is selected from the group consisting of:
 
     (a) a compound of Formula I: 
     
       
         
         
             
             
         
       
     
     wherein:
         B is C(R 1 ) 2 , O, S, or NR 1 ;   each R 1  is independently hydrogen, an amino acid side chain, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, or an arylalkyl;   R 2  is hydrogen; an alkyl; an alkenyl; an alkynyl; a cycloalkyl; a heterocyclyl; an aryl; a heteroaryl; an arylalkyl; an alpha amino acid; a beta amino acid; a peptide; a targeting moiety; a tag; —OR 5  wherein R 5  is hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, an arylalkyl, an acyl, a peptide, a targeting moiety, or a tag; —(CH 2 ) 0-1 N(R 5 ) 2  wherein each R 5  is independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, an arylalkyl, an acyl, a peptide, a targeting moiety, or a tag; or a moiety of Formula A:       

     
       
         
         
             
             
         
       
         
         
           
             
               
                 wherein:
               R 2′  is hydrogen; an alkyl; an alkenyl; an alkynyl; a cycloalkyl; a heterocyclyl; an aryl; a heteroaryl; an arylalkyl; an alpha amino acid; a beta amino acid; a peptide; a targeting moiety; a tag; —OR 5  wherein R 5  is hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, an arylalkyl, an acyl, a peptide, a targeting moiety, or a tag; or —(CH 2 ) 0-1 N(R 5 ) 2  wherein each R 5  is independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, an arylalkyl, an acyl, a peptide, a targeting moiety, or a tag;   m′ is zero or any number;   each b is independently one or two; and   c is one or two;   
             
               
             
             R 3  is hydrogen; an alkyl; an alkenyl; an alkynyl; a cycloalkyl; a heterocyclyl; an aryl; a heteroaryl; an arylalkyl; an alpha amino acid; a beta amino acid; a peptide; a targeting moiety; a tag; —OR 5  wherein R 5  is hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, an arylalkyl, an acyl, a peptide, a targeting moiety, or a tag; —N(R 5 ) 2  wherein each R 5  is independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, an arylalkyl, an acyl, a peptide, a targeting moiety, or a tag; or a moiety of Formula B: 
           
         
       
    
     
       
         
         
             
             
         
       
         
         
           
             
               
                 wherein:
               R 3′  is hydrogen; an alkyl; an alkenyl; an alkynyl; a cycloalkyl; a heterocyclyl; an aryl; a heteroaryl; an arylalkyl; an alpha amino acid; a beta amino acid; a peptide; a targeting moiety; a tag; —OR 5  wherein R 5  is hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, an arylalkyl, an acyl, a peptide, a targeting moiety, or a tag; or —N(R 5 ) 2  wherein each R 5  is independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, an arylalkyl, an acyl, a peptide, a targeting moiety, or a tag;   m″ is zero or any number; and   each d is independently one or two;   
             
               
             
             each R 4  is independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, or an arylalkyl; 
             R 4′  is hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, an arylalkyl, or a double bond between C(R 4′ , R 4 ) and B; 
             a is one or two; 
             m, n′, and n″ are each independently zero, one, two, three, or four; 
             m′″ is zero or one; 
             each o is independently one or two; and 
             p is one or two; 
           
         
       
    
     (b) a compound of Formula II: 
     
       
         
         
             
             
         
       
     
     wherein:
         each R 1  is independently hydrogen, an amino acid side chain, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, or an arylalkyl;   R 2  is hydrogen; an alkyl; an alkenyl; an alkynyl; a cycloalkyl; a heterocyclyl; an aryl; a heteroaryl; an arylalkyl; an alpha amino acid; a beta amino acid; a peptide; a targeting moiety; a tag; —OR 5  wherein R 5  is hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, an arylalkyl, an acyl, a peptide, a targeting moiety, or a tag; —(CH 2 ) 0-1 N(R 5 ) 2  wherein each R 5  is independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, an arylalkyl, an acyl, a peptide, a targeting moiety, or a tag; or a moiety of Formula A:       

     
       
         
         
             
             
         
       
         
         
           
             
               
                 wherein:
               R 2′  is hydrogen; an alkyl; an alkenyl; an alkynyl; a cycloalkyl; a heterocyclyl; an aryl; a heteroaryl; an arylalkyl; an alpha amino acid; a beta amino acid; a peptide; a targeting moiety; a tag; —OR 5  wherein R 5  is hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, an arylalkyl, an acyl, a peptide, a targeting moiety, or a tag; or —(CH 2 ) 0-1 N(R 5 ) 2  wherein each R 5  is independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, an arylalkyl, an acyl, a peptide, a targeting moiety, or a tag;   m′ is zero or any number;   each b is independently one or two; and   c is one or two;   
             
               
             
             R 3  is hydrogen; an alkyl; an alkenyl; an alkynyl; a cycloalkyl; a heterocyclyl; an aryl; a heteroaryl; an arylalkyl; an alpha amino acid; a beta amino acid; a peptide; a targeting moiety; a tag; —OR 5  wherein R 5  is hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, an arylalkyl, an acyl, a peptide, a targeting moiety, or a tag; —N(R 5 ) 2  wherein each R 5  is independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, an arylalkyl, an acyl, a peptide, a targeting moiety, or a tag; or a moiety of Formula B: 
           
         
       
    
     
       
         
         
             
             
         
       
         
         
           
             
               
                 wherein:
               R 3′  is hydrogen; an alkyl; an alkenyl; an alkynyl; a cycloalkyl; a heterocyclyl; an aryl; a heteroaryl; an arylalkyl; an alpha amino acid; a beta amino acid; a peptide; a targeting moiety; a tag; —OR 5  wherein R 5  is hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, an arylalkyl, an acyl, a peptide, a targeting moiety, or a tag; or —N(R 5 ) 2  wherein each R 5  is independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, an arylalkyl, an acyl, a peptide, a targeting moiety, or a tag;   m″ is zero or any number; and   each d is independently one or two;   
             
               
             
             n is one or four; 
             each o is independently one or two; 
             one of p′ and p″ is zero and the other is zero or one; 
             one of q′ and q″ is zero and the other is zero or one; 
             s is one, two, three, four, or five; and 
             Y—X is a hydrocarbon, an amide bond, an alkane, an alkene, an alkyne, a triazole, or a disulfide bond; and 
           
         
       
    
     (c) a compound of Formula III: 
     
       
         
         
             
             
         
       
     
     wherein:
         B is C(R 1 ) 2 , O, S, or NR 1 ;   each R 1  is independently hydrogen, an amino acid side chain, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, or an arylalkyl;   R 2  is hydrogen; an alkyl; an alkenyl; an alkynyl; a cycloalkyl; a heterocyclyl; an aryl; a heteroaryl; an arylalkyl; an alpha amino acid; a beta amino acid; a peptide; a targeting moiety; a tag; —OR 5  wherein R 5  is hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, an arylalkyl, an acyl, a peptide, a targeting moiety, or a tag; —(CH 2 ) 0-1 N(R 5 ) 2  wherein each R 5  is independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, an arylalkyl, an acyl, a peptide, a targeting moiety, or a tag; or a moiety of Formula A:       

     
       
         
         
             
             
         
       
         
         
           
             
               
                 wherein:
               R 2′  is hydrogen; an alkyl; an alkenyl; an alkynyl; a cycloalkyl; a heterocyclyl; an aryl; a heteroaryl; an arylalkyl; an alpha amino acid; a beta amino acid; a peptide; a targeting moiety; a tag; —OR 5  wherein R 5  is hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, an arylalkyl, an acyl, a peptide, a targeting moiety, or a tag; or —(CH 2 ) 0-1 N(R 5 ) 2  wherein each R 5  is independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, an arylalkyl, an acyl, a peptide, a targeting moiety, or a tag;   m′ is zero or any number;   each b is independently one or two; and   c is one or two;   
             
               
             
             R 3  is hydrogen; an alkyl; an alkenyl; an alkynyl; a cycloalkyl; a heterocyclyl; an aryl; a heteroaryl; an arylalkyl; an alpha amino acid; a beta amino acid; a peptide; a targeting moiety; a tag; —OR 5  wherein R 5  is hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, an arylalkyl, an acyl, a peptide, a targeting moiety, or a tag; —N(R 5 ) 2  wherein each R 5  is independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, an arylalkyl, an acyl, a peptide, a targeting moiety, or a tag; or a moiety of Formula B: 
           
         
       
    
     
       
         
         
             
             
         
       
         
         
           
             
               
                 wherein:
               R 3′  is hydrogen; an alkyl; an alkenyl; an alkynyl; a cycloalkyl; a heterocyclyl; an aryl; a heteroaryl; an arylalkyl; an alpha amino acid; a beta amino acid; a peptide; a targeting moiety; a tag; —OR 5  wherein R 5  is hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, an arylalkyl, an acyl, a peptide, a targeting moiety, or a tag; or —N(R 5 ) 2  wherein each R 5  is independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, an arylalkyl, an acyl, a peptide, a targeting moiety, or a tag;   m″ is zero or any number; and   each d is independently one or two;   
             
               
             
             each R 4  is independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, or an arylalkyl; 
             R 4′  is hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, an arylalkyl, or a double bond between C(R 4′ , R 4 ) and B; 
             m, n′, and n″ are each independently zero, one, two, three, or four; 
             n is one or four; 
             each o is independently one or two; 
             p is one or two; 
             one of p′ and p″ is zero and the other is zero or one; 
             one of q′ and q″ is zero and the other is zero or one; 
             s is one, two, three, four, or five; and 
             Y—X is a hydrocarbon, an amide bond, an alkane, an alkene, an alkyne, a triazole, or a disulfide bond. 
           
         
       
    
     A second aspect of the present invention relates to a method of modulating transcription of a gene in a cell, where transcription of the gene is mediated by interaction of hypoxia-inducible factor 1α (“HIF-1α”) with coactivator protein p300 (or the homologous CREB binding protein, CBP). This method involves contacting the cell with a peptidomimetic described herein under conditions effective to modulate transcription of the gene. 
     A third aspect of the present invention relates to a method of treating or preventing in a subject a disorder mediated by interaction of HIF-1α with CBP and/or p300. This method involves administering a peptidomimetic described herein to the subject under conditions effective to treat or prevent the disorder. 
     A fourth aspect of the present invention relates to a method of reducing or preventing angiogenesis in a tissue. This method involves contacting the tissue with a peptidomimetic described herein under conditions effective to reduce or prevent angiogenesis in the tissue. 
     A fifth aspect of the present invention relates to a method of decreasing survival and/or proliferation of a cell under hypoxic conditions. This method involves contacting the cell with a peptidomimetic described herein under conditions effective to decrease survival and/or proliferation of the cell. 
     A sixth aspect of the present invention relates to a method of identifying a potential ligand of CBP and/or p300. This method involves providing a peptidomimetic described herein, contacting the peptidomimetic with a test agent, and detecting whether the test agent selectively binds to the peptidomimetic. A test agent that selectively binds to the peptidomimetic is identified as a potential ligand of CBP and/or p300. 
     Selective blockade of gene expression by designed small molecules is a fundamental challenge at the interface of chemistry, biology, and medicine. Transcription factors have been among the most elusive targets in genetics and drug discovery, but the fields of chemical biology and genetics have evolved to a point where this task can be addressed. The design, synthesis, and in vivo efficacy evaluation of a protein domain mimetic targeting the interaction of the p300/CBP coactivator with the transcription factor HIF-1α is described herein. As indicated herein, disrupting this interaction results in a rapid down-regulation of hypoxia-inducible genes critical for cancer progression. The observed effects were compound-specific and dose-dependent. Gene expression profiling with oligonucleotide microarrays revealed effective inhibition of hypoxia-inducible genes with relatively minimal perturbation of non-targeted signaling pathways. Remarkable efficacy of the compound HBS 1 in suppressing tumor growth was observed in the fully established murine xenograft models of renal cell carcinoma of the clear cell type (RCC). These results suggest that rationally designed synthetic mimics of protein subdomains that target the transcription factor-coactivator interfaces represent a novel approach for in vivo modulation of oncogenic signaling and arresting tumor growth. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         FIG. 1A  is a schematic diagram illustrating the structure of the complex of the C-terminal transactivation domain (“C-TAD”) of the hypoxia-inducible factor 1α (“HIF-1α”) with cysteine-histidine rich 1 domain (“CH1”) of the coactivator protein p300 (or the homologous CREB binding protein, CBP) (Lepourcelet et al., “Small-Molecule Antagonists of the Oncogenic Tcf/β-Catenin Protein Complex,”  Cancer Cell  5:91-102 (2004); Vassilev et al., “In Vivo Activation of the p53 Pathway by Small-Molecule Antagonists of MDM2 ,” Science  303:844-48 (2004), which are hereby incorporated by reference in their entirety).  FIG. 1B  is the domain map of HIF-1α showing the basic helix-loop-helix region (“bHLH”), PAS, the N-terminal transactivation domain (“N-TAD”), and the C-TAD. The human HIF-1α C-TAD sequence (SEQ ID NO: 1) is shown in  FIG. 1C , along with the location of the αA and αB helices. 
         FIG. 2  is a schematic diagram illustrating the HIF-1α pathway. ARNT: aryl hydrocarbon receptor nuclear translocator; VHL: von Hippel-Lindau tumor suppressor; HRE: hypoxia response element; VEGF: vascular endothelial growth factor. 
         FIGS. 3A-C  are schematic diagrams relating to the regulation of transcription by HIF-1α and CBP/p300. As shown in  FIG. 3A , transcription of hypoxia-inducible genes is controlled by the interaction of HRE-bound HIF-1α/ARNT heterodimer with transcriptional coactivator CBP/p300. Protein domain mimetics should competitively inhibit the interaction and associated gene expression (see  FIG. 3B ). As shown in  FIG. 3C , the C-TAD 793-826  domain of HIF-1α(SEQ ID NO: 2) utilizes helical motifs to target the cysteine-histidine rich 1 (CH1) region of CBP/p300. HIF-1α is shown in gold and CBP/p300 in gray (PDB code 1L8C). 
         FIGS. 4A-C  are analytical HPLC traces of HBS 1 ( FIG. 4A ), HBS 2 ( FIG. 4B ), and peptide 3 ( FIG. 4C ). 
         FIGS. 5A-C  show that HBS 1 targets p300-CH1 with high affinity and inhibits its binding to HIF-1α C-TAD 786-826 .  FIG. 5A  is a graph of the affinity of HBS 1, HBS 2, peptide 3, and HIF-1αC-TAD 786-826  for the CH1 domain as determined by tryptophan fluorescence spectroscopy.  FIG. 5B  is a molecular model that depicts the results of a  1 H- 15 N HSQC NMR titration experiment. The p300-CH1 residues undergoing chemical shift perturbations upon addition of HBS 1 are color-mapped, matching the magnitude of the chemical shift changes. HIF-1α helix B is shown in gold. The model was refined from the NMR structure of the HIF-1α/p300 complex (PDB code 1L8C).  FIG. 5C  is a graph of the results of fluorescence anisotropy experiments, showing the ability of HBS 1 to inhibit CH1 Flu /HIF C-TAD 786-826  complex formation. 
         FIGS. 6A-B  show the structures of stabilized helices and linear peptide. HBS 1 ( FIG. 6A , left panel) mimics the αB domain of HIF-1α and features four residues that contribute significantly to binding (L818, L822, L823 and L824). HBS 2 ( FIG. 6A , right panel) was designed to be a specificity control; this compound is identical to HBS 1 with the exception of L822, which was mutated to an alanine group. Peptide 3 ( FIG. 6B ) (SEQ ID NO: 3) is an unconstrained negative control with the amino acid sequence that repeats that of HBS 1. 
         FIG. 7  is the circular dichroism spectra of HBS 1, HBS 2, and peptide 3. CD studies were performed with 50-100 μM peptide solutions in 10 mM KF (pH 7.4). 
         FIGS. 8A-D  are  1 H- 15 N HSQC spectra of the p300-CH1 domain with different concentrations of Zn 2+ .  FIG. 8A  is the spectra of misfolded p300-CH1:Zn 2+  (1:&lt;3).  FIG. 8B  is the spectra of folded p300-CH1:Zn 2+  (1:3).  FIG. 8C  is the spectra of unfolded p300-CH1:Zn 2+  with excess Zn 2+  (1:6).  FIG. 8D  is the spectra of refolded p300-CH1:Zn 2+  with EDTA to remove the excess of Zn 2+  (1:3). 
         FIG. 9  is a schematic diagram of the HIF-1α/p300-CH1 interaction. Tryptophan-403 resides in the hydrophobic groove targeted by the HIF-1α αB helix. (PDB code 1L8C.) 
         FIG. 10  is a graph showing the concentration-dependent changes in the fluorescence spectra of the CH1 domain (1 μM) upon titration of HBS 1. 
         FIG. 11  shows the chemical structure of fluorescein-labeled C-TAD (Flu-HIF-1α C-TAD 786-826 ). (Mass [M+H] calc&#39;d=4977.1. found=4976.8.) 
         FIG. 12  is a graph of the binding of Flu-HIF C-TAD to p300-CH1 as monitored by a fluorescence polarization assay. 
         FIG. 13  is the overlaid  1 H- 15 N HSQC titration spectra of p300-CH1 (blue), CH1:HBS 1 (1:5, red), and CH1:HBS 1 (1:10, green). 
         FIG. 14  is a mean chemical shift difference (ΔδNTH) plot depicting changes in residues of p300-CH1 upon binding with HBS 1. 
         FIG. 15  is a graph of the results from the luciferase-based promoter activity assay with MDA-MB-231-HRE-Luc cell line treated with HBS 1, HBS 2 (specificity control), or peptide 3. Hypoxia was mimicked with GasPak EZ pouch (300 μM). Error bars represent ±s.e.m. of experiments performed in quadruplicate. * P&lt;0.05, t-test. The results demonstrate that HBS 1 reduces HIF-1α inducible promoter activity in vitro. 
         FIG. 16  is a western blot analysis of HIF-1α levels in the nuclear and cytoplasmic extracts of HeLa cells. Cells were incubated for a total of 24 hours with HBS 1. After 6 hours, hypoxia was mimicked with DFO (300 μM) for an additional 18 hours. The results demonstrate that HBS 1 does not affect the intracellular levels of HIF-1α. 
         FIGS. 17A-D  show that HBS 1 down-regulates hypoxia-induced transcription in cell culture. As shown in  FIGS. 17A-C , HBS 1 reduced expression levels of VEGFA ( FIG. 17A ), SLC2A1 (GLUT1) ( FIG. 17B ), and LOX ( FIG. 17C ) in a dose-dependent manner in HeLa cells under hypoxia conditions as measured by real-time qRT-PCR. Hypoxia was mimicked with DFO (300 μM). HBS 2 and peptide 3 show reduced inhibitory activities at the same concentrations. Error bars are ±s.e.m. of four independent experiments. ** P&lt;0.01, * P&lt;0.05, t-test.  FIG. 17D  is a graph comparing the efficacies of HBS 1 in down-regulating expression levels of VEGFA in HeLa cells under two different hypoxia-mimetic conditions (DFO and hypoxia bag) as measured by real-time qRT-PCR. For each experiment under hypoxia-mimetic conditions, mRNA levels were normalized to VEGFA mRNA levels found in the vehicle-treated normoxic cells. 
         FIG. 18  is a graph of VEGF protein levels under hypoxia or normoxia, with or without treatment with varying concentrations of HBS 1. Hypoxia was mimicked with 300 μM DFO. Error bars represent ±s.e.m of experiments performed in triplicate. * P&lt;0.05, t-test. The results demonstrate that HBS 1 reduces levels of secreted VEGF protein in HeLa cells in a dose-dependent manner. 
         FIG. 19  is a graph of the results from MTT assays with HeLa cells treated with HBS 1, HBS 2, or peptide 1 in a concentration range of 1 μM and 100 μM for 24 hours. The results demonstrate that HBS 1 shows low cytotoxicity in HeLa cells. 
         FIGS. 20A-C  show the results from gene expression profiling obtained with Affymetrix Human Gene ST 1.0 arrays.  FIG. 20A  shows the hierarchical agglomerative clustering of 368 transcripts induced or repressed 2-fold or more (one-way ANOVA, P&lt;0.05) by 300 μM DFO under the three specified conditions: no treatment (“-”), treatment with 50 μM HBS 1 (“1”), and treatment with 50 μM HBS 2 (“2”). Clustering was based on a Pearson centered correlation of intensity ratios for each treatment compared to DFO-induced cells (controls) using average-linkage as a distance. Of this DFO-induced set, 92 were inhibited and 30 were induced by HBS 1, whereas 81 were inhibited and 70 induced by HBS 2 (|fold-change|≧1.1, P&lt;0.05).  FIG. 20B  shows a clustering of expression changes of the 45 transcripts induced or repressed 4-fold or more (P&lt;0.05) by 300 μM DFO or by the treatments under the designated treatment conditions. Clustering parameters were the same as in  FIG. 20A .  FIG. 20C  shows Venn diagrams representing transcripts down- and up-regulated (|fold-change|≧1.1, P&lt;0.05) by HBS 1 and HBS 2. Numbers inside the intersections represent DFO-induced transcripts affected by both treatments. 
         FIG. 21  shows the plasma concentration versus time curves for HBS 1 and control peptide 3 in BALB/c mice. 
         FIGS. 22A-C  demonstrate that HBS 1 suppresses tumor growth in mouse xenograft models.  FIG. 22A  is a box-whisker diagram of tumor volumes measured throughout the study with boxes representing the upper and lower quartiles and median and error bars showing maximum and minimum volumes. Tumors from mice treated with HBS 1 were smaller (median volume: 138 mm 3 ) than those of the control mice (median: 293 mm 3 ).  FIG. 22B  is a graph showing the results of the weight measurements of control- and HBS 1-treated mice throughout the entire duration of the experiments, showing the absence of toxicity-related weight loss.  FIG. 22C  shows images of mice injected with the tumor-accumulating near-infrared (NIR) contrast agent. Mice from the HBS 1 treated group show significantly lower intensity of the NIR signal as compared to the control group, demonstrating that HBS 1 lowers overall tumor burden in mice. 
     
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     Transcription factors are among the most challenging, but attractive targets, for drug discovery (Rutledge et al., “Molecular Recognition of Protein Surfaces: High Affinity Ligands for the CBPKIX Domain,”  J. Am. Chem. Soc.  125(47):14336-47 (2003), which is hereby incorporated by reference in its entirety). High-resolution structures of transcription factors in complex with protein partners offer a foundation for rational drug design strategies. Although many transcription factors exhibit significant intrinsic disorder, their complexes with coactivator proteins often feature discrete protein secondary structures (Rutledge et al., “Molecular Recognition of Protein Surfaces: High Affinity Ligands for the CBPKIX Domain,”  J. Am. Chem. Soc.  125(47):14336-47 (2003), which is hereby incorporated by reference in its entirety), such as α-helices, that contribute significantly to binding and may be used as templates for rational drug design (Semenza, “Targeting HIF-1 for Cancer Therapy,”  Nat. Rev. Cancer  3(10):721-32 (2003), which is hereby incorporated by reference in its entirety). Described herein is the design of stabilized peptide α-helices that can modulate transcription of hypoxia inducible genes by interfering with interactions of the C-terminal activation domain (“C-TAD”) of hypoxia inducible factor-1α (“HIF-1α”) and the cysteine-histidine rich 1 (“CH1”) domain of the coactivator protein p300 (or the homologous CREB binding protein, CBP) ( FIGS. 3A-C ) (O&#39;Rourke et al., “Identification of Hypoxically Inducible mRNAs in HeLa Cells Using Differential-Display PCR: Role of Hypoxia-Inducible Factor-1 ,” Eur. J. Biochem.  241(2):403-10 (1996); Freedman et al., “Structural Basis for Recruitment of CBP/p300 by Hypoxia-Inducible Factor-1 Alpha,”  Proc. Nat&#39;l Acad. Sci. U.S.A . 99(8):5367-72 (2002), which are hereby incorporated by reference in their entirety). As shown herein, an optimized mimic of HIF-1αC-TAD, HBS 1, a high affinity ligand of CH1, can downregulate target genes under hypoxic conditions without affecting the endogenous levels of HIF-1α. HBS 1 does not adversely affect cell growth at high concentrations, which suggests that the compound is generally non-toxic to normoxic cells. This constrained α-helix retains significant activity in mouse plasma as compared to its unconstrained peptide analog (peptide 3) highlighting the ability of stabilized helices to evade serum proteases. The genome-wide effects of HIF-1αC-TAD mimic 1 and a negative control (HBS 2) were compared using gene expression profiling. The results show that HBS 1 modulates expression of a select set of genes, many of which are of direct relevance to the predicted pathways. Lastly, the ability of HBS 1 to control tumor progression in a mouse tumor xenograft model was examined. The synthetic helix was found to provide rapid and effective regression of tumor growth. These results support the hypothesis that functional mimics of protein subdomains that mediate interactions between partner proteins offer an attractive strategy for inhibitor design. It is predicted that other such peptidomimetics of the αB helix of HIF-1α would have similar effects. 
     The present invention relates to a peptidomimetic, wherein the peptidomimetic: 
     (i) mimics a helix having the formula X 1 —X 2 —X 2 —X 3 —X 2 —X 2 —X 1 —X 4 —X 5 , wherein each X 1  is any negatively charged residue, each X 2  is any hydrophobic residue, X 3  is any positively-charged residue, X 4  is any polar residue, and X 5  is absent or any hydrophobic residue; and
 
(ii) is selected from the group consisting of:
 
     (a) a compound of Formula I: 
     
       
         
         
             
             
         
       
     
     wherein:
         B is C(R 1 ) 2 , O, S, or NR 1 ;   each R 1  is independently hydrogen, an amino acid side chain, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, or an arylalkyl;   R 2  is hydrogen; an alkyl; an alkenyl; an alkynyl; a cycloalkyl; a heterocyclyl; an aryl; a heteroaryl; an arylalkyl; an alpha amino acid; a beta amino acid; a peptide; a targeting moiety; a tag; —OR 5  wherein R 5  is hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, an arylalkyl, an acyl, a peptide, a targeting moiety, or a tag; —(CH 2 ) 0-1 N(R 5 ) 2  wherein each R 5  is independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, an arylalkyl, an acyl, a peptide, a targeting moiety, or a tag; or a moiety of Formula A:       

     
       
         
         
             
             
         
       
         
         
           
             
               
                 wherein:
               R 2′  is hydrogen; an alkyl; an alkenyl; an alkynyl; a cycloalkyl; a heterocyclyl; an aryl; a heteroaryl; an arylalkyl; an alpha amino acid; a beta amino acid; a peptide; a targeting moiety; a tag; —OR 5  wherein R 5  is hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, an arylalkyl, an acyl, a peptide, a targeting moiety, or a tag; or —(CH 2 ) 0-1 N(R 5 ) 2  wherein each R 5  is independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, an arylalkyl, an acyl, a peptide, a targeting moiety, or a tag;   m′ is zero or any number;   each b is independently one or two; and   c is one or two;   
             
               
             
             R 3  is hydrogen; an alkyl; an alkenyl; an alkynyl; a cycloalkyl; a heterocyclyl; an aryl; a heteroaryl; an arylalkyl; an alpha amino acid; a beta amino acid; a peptide; a targeting moiety; a tag; —OR 5  wherein R 5  is hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, an arylalkyl, an acyl, a peptide, a targeting moiety, or a tag; —N(R 5 ) 2  wherein each R 5  is independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, an arylalkyl, an acyl, a peptide, a targeting moiety, or a tag; or a moiety of Formula B: 
           
         
       
    
     
       
         
         
             
             
         
       
         
         
           
             
               
                 wherein:
               R 3′  is hydrogen; an alkyl; an alkenyl; an alkynyl; a cycloalkyl; a heterocyclyl; an aryl; a heteroaryl; an arylalkyl; an alpha amino acid; a beta amino acid; a peptide; a targeting moiety; a tag; —OR 5  wherein R 5  is hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, an arylalkyl, an acyl, a peptide, a targeting moiety, or a tag; or —N(R 5 ) 2  wherein each R 5  is independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, an arylalkyl, an acyl, a peptide, a targeting moiety, or a tag;   m″ is zero or any number; and   each d is independently one or two;   
             
               
             
             each R 4  is independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, or an arylalkyl; 
             R 4′  is hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, an arylalkyl, or a double bond between C(R 4′ , R 4 ) and B; 
             a is one or two; 
             m, n′, and n″ are each independently zero, one, two, three, or four; 
             m′″ is zero or one; 
             each o is independently one or two; and 
             p is one or two; 
           
         
       
    
     (b) a compound of Formula II: 
     
       
         
         
             
             
         
       
     
     wherein:
         each R 1  is independently hydrogen, an amino acid side chain, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, or an arylalkyl;   R 2  is hydrogen; an alkyl; an alkenyl; an alkynyl; a cycloalkyl; a heterocyclyl; an aryl; a heteroaryl; an arylalkyl; an alpha amino acid; a beta amino acid; a peptide; a targeting moiety; a tag; —OR 5  wherein R 5  is hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, an arylalkyl, an acyl, a peptide, a targeting moiety, or a tag; —(CH 2 ) 0-1 N(R 5 ) 2  wherein each R 5  is independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, an arylalkyl, an acyl, a peptide, a targeting moiety, or a tag; or a moiety of Formula A:       

     
       
         
         
             
             
         
       
         
         
           
             
               
                 wherein:
               R 2′  is hydrogen; an alkyl; an alkenyl; an alkynyl; a cycloalkyl; a heterocyclyl; an aryl; a heteroaryl; an arylalkyl; an alpha amino acid; a beta amino acid; a peptide; a targeting moiety; a tag; —OR 5  wherein R 5  is hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, an arylalkyl, an acyl, a peptide, a targeting moiety, or a tag; or —(CH 2 ) 0-1 N(R 5 ) 2  wherein each R 5  is independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, an arylalkyl, an acyl, a peptide, a targeting moiety, or a tag;   m′ is zero or any number;   each b is independently one or two; and   c is one or two;   
             
               
             
             R 3  is hydrogen; an alkyl; an alkenyl; an alkynyl; a cycloalkyl; a heterocyclyl; an aryl; a heteroaryl; an arylalkyl; an alpha amino acid; a beta amino acid; a peptide; a targeting moiety; a tag; —OR 5  wherein R 5  is hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, an arylalkyl, an acyl, a peptide, a targeting moiety, or a tag; —N(R 5 ) 2  wherein each R 5  is independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, an arylalkyl, an acyl, a peptide, a targeting moiety, or a tag; or a moiety of Formula B: 
           
         
       
    
     
       
         
         
             
             
         
       
         
         
           
             
               
                 wherein:
               R 3′  is hydrogen; an alkyl; an alkenyl; an alkynyl; a cycloalkyl; a heterocyclyl; an aryl; a heteroaryl; an arylalkyl; an alpha amino acid; a beta amino acid; a peptide; a targeting moiety; a tag; —OR 5  wherein R 5  is hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, an arylalkyl, an acyl, a peptide, a targeting moiety, or a tag; or —N(R 5 ) 2  wherein each R 5  is independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, an arylalkyl, an acyl, a peptide, a targeting moiety, or a tag;   m″ is zero or any number; and   each d is independently one or two;   
             
               
             
             n is one or four; 
             each o is independently one or two; 
             one of p′ and p″ is zero and the other is zero or one; 
             one of q′ and q″ is zero and the other is zero or one; 
             s is one, two, three, four, or five; and 
             Y—X is a hydrocarbon, an amide bond, an alkane, an alkene, an alkyne, a triazole, or a disulfide bond; and 
           
         
       
    
     (c) a compound of Formula III: 
     
       
         
         
             
             
         
       
     
     wherein:
         B is C(R 1 ) 2 , O, S, or NR 1 ;   each R 1  is independently hydrogen, an amino acid side chain, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, or an arylalkyl;   R 2  is hydrogen; an alkyl; an alkenyl; an alkynyl; a cycloalkyl; a heterocyclyl; an aryl; a heteroaryl; an arylalkyl; an alpha amino acid; a beta amino acid; a peptide; a targeting moiety; a tag; —OR 5  wherein R 5  is hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, an arylalkyl, an acyl, a peptide, a targeting moiety, or a tag; —(CH 2 ) 0-1 N(R 5 ) 2  wherein each R 5  is independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, an arylalkyl, an acyl, a peptide, a targeting moiety, or a tag; or a moiety of Formula A:       

     
       
         
         
             
             
         
       
         
         
           
             
               
                 wherein:
               R 2′  is hydrogen; an alkyl; an alkenyl; an alkynyl; a cycloalkyl; a heterocyclyl; an aryl; a heteroaryl; an arylalkyl; an alpha amino acid; a beta amino acid; a peptide; a targeting moiety; a tag; —OR 5  wherein R 5  is hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, an arylalkyl, an acyl, a peptide, a targeting moiety, or a tag; or —(CH 2 ) 0-1 N(R 5 ) 2  wherein each R 5  is independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, an arylalkyl, an acyl, a peptide, a targeting moiety, or a tag;   m′ is zero or any number;   each b is independently one or two; and   c is one or two;   
             
               
             
             R 3  is hydrogen; an alkyl; an alkenyl; an alkynyl; a cycloalkyl; a heterocyclyl; an aryl; a heteroaryl; an arylalkyl; an alpha amino acid; a beta amino acid; a peptide; a targeting moiety; a tag; —OR 5  wherein R 5  is hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, an arylalkyl, an acyl, a peptide, a targeting moiety, or a tag; —N(R 5 ) 2  wherein each R 5  is independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, an arylalkyl, an acyl, a peptide, a targeting moiety, or a tag; or a moiety of Formula B: 
           
         
       
    
     
       
         
         
             
             
         
       
         
         
           
             
               
                 wherein:
               R 3′  is hydrogen; an alkyl; an alkenyl; an alkynyl; a cycloalkyl; a heterocyclyl; an aryl; a heteroaryl; an arylalkyl; an alpha amino acid; a beta amino acid; a peptide; a targeting moiety; a tag; —OR 5  wherein R 5  is hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, an arylalkyl, an acyl, a peptide, a targeting moiety, or a tag; or —N(R 5 ) 2  wherein each R 5  is independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, an arylalkyl, an acyl, a peptide, a targeting moiety, or a tag;   m″ is zero or any number; and   each d is independently one or two;   
             
               
             
             each R 4  is independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, or an arylalkyl; 
             R 4′  is hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, an arylalkyl, or a double bond between C(R 4′ , R 4 ) and B; 
             m, n′, and n″ are each independently zero, one, two, three, or four; 
             n is one or four; 
             each o is independently one or two; 
             p is one or two; 
             one of p′ and p″ is zero and the other is zero or one; 
             one of q′ and q″ is zero and the other is zero or one; 
             s is one, two, three, four, or five; and 
             Y—X is a hydrocarbon, an amide bond, an alkane, an alkene, an alkyne, a triazole, or a disulfide bond. 
           
         
       
    
     Amino acid side chains according to this and all aspects of the present invention can be any amino acid side chain from natural or nonnatural amino acids, including from alpha amino acids, beta amino acids, gamma amino acids, L-amino acids, and D-amino acids. 
     As used herein, the term “alkyl” means an aliphatic hydrocarbon group which may be straight or branched having about 1 to about 6 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl, or propyl are attached to a linear alkyl chain. Exemplary alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, n-pentyl, and 3-pentyl. 
     The term “alkenyl” means an aliphatic hydrocarbon group containing a carbon-carbon double bond and which may be straight or branched having about 2 to about 6 carbon atoms in the chain. Preferred alkenyl groups have 2 to about 4 carbon atoms in the chain. Exemplary alkenyl groups include ethenyl, propenyl, n-butenyl, and i-butenyl. 
     The term “alkynyl” means an aliphatic hydrocarbon group containing a carbon-carbon triple bond and which may be straight or branched having about 2 to about 6 carbon atoms in the chain. Preferred alkynyl groups have 2 to about 4 carbon atoms in the chain. Exemplary alkynyl groups include ethynyl, propynyl, n-butynyl, 2-butynyl, 3-methylbutynyl, and n-pentynyl. 
     As used herein, the term “cycloalkyl” refers to a non-aromatic saturated or unsaturated mono- or polycyclic ring system which may contain 3 to 6 carbon atoms, and which may include at least one double bond. Exemplary cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, anti-bicyclopropane, or syn-bicyclopropane. 
     As used herein, the term “heterocyclyl” refers to a stable 3- to 18-membered ring system that consists of carbon atoms and from one to five heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. The heterocyclyl may be a monocyclic or a polycyclic ring system, which may include fused, bridged, or spiro ring systems; and the nitrogen, carbon, or sulfur atoms in the heterocyclyl may be optionally oxidized; the nitrogen atom may be optionally quaternized; and the ring may be partially or fully saturated. Representative monocyclic heterocyclyls include piperidine, piperazine, pyrimidine, morpholine, thiomorpholine, pyrrolidine, tetrahydrofuran, pyran, tetrahydropyran, oxetane, and the like. Representative polycyclic heterocyclyls include indole, isoindole, indolizine, quinoline, isoquinoline, purine, carbazole, dibenzofuran, chromene, xanthene, and the like. 
     As used herein, the term “aryl” refers to an aromatic monocyclic or polycyclic ring system containing from 6 to 19 carbon atoms, where the ring system may be optionally substituted. Aryl groups of the present invention include, but are not limited to, groups such as phenyl, naphthyl, azulenyl, phenanthrenyl, anthracenyl, fluorenyl, pyrenyl, triphenylenyl, chrysenyl, and naphthacenyl. 
     As used herein, “heteroaryl” refers to an aromatic ring radical which consists of carbon atoms and from one to five heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. Examples of heteroaryl groups include, without limitation, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, furyl, thiophenyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thienopyrrolyl, furopyrrolyl, indolyl, azaindolyl, isoindolyl, indolinyl, indolizinyl, indazolyl, benzimidazolyl, imidazopyridinyl, benzotriazolyl, benzoxazolyl, benzoxadiazolyl, benzothiazolyl, pyrazolopyridinyl, triazolopyridinyl, thienopyridinyl, benzothiadiazolyl, benzofuyl, benzothiophenyl, quinolinyl, isoquinolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, cinnolinyl, quinazolinyl, quinolizilinyl, phthalazinyl, benzotriazinyl, chromenyl, naphthyridinyl, acrydinyl, phenanzinyl, phenothiazinyl, phenoxazinyl, pteridinyl, and purinyl. Additional heteroaryls are described in C OMPREHENSIVE  H ETEROCYCLIC  C HEMISTRY : T HE  S TRUCTURE , R EACTIONS , S YNTHESIS AND  U SE OF  H ETEROCYCLIC  COMPOUNDS (Katritzky et al. eds., 1984), which is hereby incorporated by reference in its entirety. 
     The term “arylalkyl” refers to a moiety of the formula —R a R b  where R a  is an alkyl or cycloalkyl as defined above and R b  is an aryl or heteroaryl as defined above. 
     As used herein, the term “acyl” means a moiety of formula R-carbonyl, where R is an alkyl, cycloalkyl, aryl, or heteroaryl as defined above. Exemplary acyl groups include formyl, acetyl, propanoyl, benzoyl, and propenoyl. 
     An amino acid according to this and all aspects of the present invention can be any natural or non-natural amino acid. 
     A “peptide” as used herein is any oligomer of two or more natural or non-natural amino acids, including alpha amino acids, beta amino acids, gamma amino acids, L-amino acids, D-amino acids, and combinations thereof. In preferred embodiments, the peptide is ˜5 to ˜30 (e.g., ˜5 to ˜10, ˜5 to ˜17, ˜10 to ˜17, ˜10 to ˜30, or ˜18 to ˜30) amino acids in length. Typically, the peptide is 10-17 amino acids in length. In a preferred embodiment, the peptide contains a mixture of alpha and beta amino acids in the pattern α3/β1 (this is particularly preferred for α-helix mimetics). 
     A “tag” as used herein includes any labeling moiety that facilitates the detection, quantitation, separation, and/or purification of the compounds of the present invention. Suitable tags include purification tags, radioactive or fluorescent labels, and enzymatic tags. 
     Purification tags, such as poly-histidine (His 6- ), a glutathione-S-transferase (GST-), or maltose-binding protein (MBP-), can assist in compound purification or separation but can later be removed, i.e., cleaved from the compound following recovery. Protease-specific cleavage sites can be used to facilitate the removal of the purification tag. The desired product can be purified further to remove the cleaved purification tags. 
     Other suitable tags include radioactive labels, such as,  125 I,  131 I,  111 In, or  99 TC. Methods of radiolabeling compounds are known in the art and described in U.S. Pat. No. 5,830,431 to Srinivasan et al., which is hereby incorporated by reference in its entirety. Radioactivity is detected and quantified using a scintillation counter or autoradiography. Alternatively, the compound can be conjugated to a fluorescent tag. Suitable fluorescent tags include, without limitation, chelates (europium chelates), fluorescein and its derivatives, rhodamine and its derivatives, dansyl, Lissamine, phycoerythrin, and Texas Red. The fluorescent labels can be conjugated to the compounds using techniques disclosed in C URRENT  P ROTOCOLS IN  I MMUNOLOGY  (Coligen et al. eds., 1991), which is hereby incorporated by reference in its entirety. Fluorescence can be detected and quantified using a fluorometer. 
     Enzymatic tags generally catalyze a chemical alteration of a chromogenic substrate which can be measured using various techniques. For example, the enzyme may catalyze a color change in a substrate, which can be measured spectrophotometrically. Alternatively, the enzyme may alter the fluorescence or chemiluminescence of the substrate. Examples of suitable enzymatic tags include luciferases (e.g., firefly luciferase and bacterial luciferase; see e.g., U.S. Pat. No. 4,737,456 to Weng et al., which is hereby incorporated by reference in its entirety), luciferin, 2,3-dihydrophthalazinediones, malate dehydrogenase, urease, peroxidases (e.g., horseradish peroxidase), alkaline phosphatase, β-galactosidase, glucoamylase, lysozyme, saccharide oxidases (e.g., glucose oxidase, galactose oxidase, and glucose-6-phosphate dehydrogenase), heterocyclic oxidases (e.g., uricase and xanthine oxidase), lactoperoxidase, microperoxidase, and the like. Techniques for conjugating enzymes to proteins and peptides are described in O&#39;Sullivan et al., Methods for the Preparation of Enzyme—Antibody Conjugates for Use in Enzyme Immunoassay, in M ETHODS IN  E NZYMOLOGY  147-66 (Langone et al. eds., 1981), which is hereby incorporated by reference in its entirety. 
     A targeting moiety according to the present invention functions to (i) promote the cellular uptake of the compound, (ii) target the compound to a particular cell or tissue type (e.g., signaling peptide sequence), or (iii) target the compound to a specific sub-cellular localization after cellular uptake (e.g., transport peptide sequence). 
     To promote the cellular uptake of a compound of the present invention, the targeting moiety may be a cell penetrating peptide (CPP). CPPs translocate across the plasma membrane of eukaryotic cells by a seemingly energy-independent pathway and have been used successfully for intracellular delivery of macromolecules, including antibodies, peptides, proteins, and nucleic acids, with molecular weights several times greater than their own. Several commonly used CPPs, including polyarginines, transportant, protamine, maurocalcine, and M918, are suitable targeting moieties for use in the present invention and are well known in the art (see Stewart et al., “Cell-Penetrating Peptides as Delivery Vehicles for Biology and Medicine,”  Organic Biomolecular Chem.  6:2242-55 (2008), which is hereby incorporated by reference in its entirety). Additionally, methods of making CPP are described in U.S. Patent Application Publication No. 20080234183 to Hallbrink et al., which is hereby incorporated by reference in its entirety. 
     Another suitable targeting moiety useful for enhancing the cellular uptake of a compound is an “importation competent” signal peptide as disclosed by U.S. Pat. No. 6,043,339 to Lin et al., which is hereby incorporated by reference in its entirety. An importation competent signal peptide is generally about 10 to about 50 amino acid residues in length—typically hydrophobic residues—that render the compound capable of penetrating through the cell membrane from outside the cell to the interior of the cell. An exemplary importation competent signal peptide includes the signal peptide from Kaposi fibroblast growth factor (see U.S. Pat. No. 6,043,339 to Lin et al., which is hereby incorporated by reference in its entirety). Other suitable peptide sequences can be selected from the SIGPEP database (see von Heijne G., “SIGPEP: A Sequence Database for Secretory Signal Peptides,”  Protein Seq. Data Anal.  1(1):41-42 (1987), which is hereby incorporated by reference in its entirety). 
     Another suitable targeting moiety is a signal peptide sequence capable of targeting the compounds of the present invention to a particular tissue or cell type. The signaling peptide can include at least a portion of a ligand binding protein. Suitable ligand binding proteins include high-affinity antibody fragments (e.g., Fab, Fab′ and F(ab) 2 , single-chain Fv antibody fragments), nanobodies or nanobody fragments, fluorobodies, or aptamers. Other ligand binding proteins include biotin-binding proteins, lipid-binding proteins, periplasmic binding proteins, lectins, serum albumins, enzymes, phosphate and sulfate binding proteins, immunophilins, metallothionein, or various other receptor proteins. For cell specific targeting, the signaling peptide is preferably a ligand binding domain of a cell specific membrane receptor. Thus, when the modified compound is delivered intravenously or otherwise introduced into blood or lymph, the compound will adsorb to the targeted cell, and the targeted cell will internalize the compound. For example, if the target cell is a cancer cell, the compound may be conjugated to an anti-C3B(I) antibody as disclosed by U.S. Pat. No. 6,572,856 to Taylor et al., which is hereby incorporated by reference in its entirety. Alternatively, the compound may be conjugated to an alphafeto protein receptor as disclosed by U.S. Pat. No. 6,514,685 to Moro, which is hereby incorporated by reference in its entirety, or to a monoclonal GAH antibody as disclosed by U.S. Pat. No. 5,837,845 to Hosokawa, which is hereby incorporated by reference in its entirety. For targeting a compound to a cardiac cell, the compound may be conjugated to an antibody recognizing elastin microfibril interfacer (EMILIN2) (Van Hoof et al., “Identification of Cell Surface for Antibody-Based Selection of Human Embryonic Stem Cell-Derived Cardiomyocytes,”  J Proteom Res  9:1610-18 (2010), which is hereby incorporated by reference in its entirety), cardiac troponin I, connexin-43, or any cardiac cell-surface membrane receptor that is known in the art. For targeting a compound to a hepatic cell, the signaling peptide may include a ligand domain specific to the hepatocyte-specific asialoglycoprotein receptor. Methods of preparing such chimeric proteins and peptides are described in U.S. Pat. No. 5,817,789 to Heartlein et al., which is hereby incorporated by reference in its entirety. 
     Another suitable targeting moiety is a transport peptide that directs intracellular compartmentalization of the compound once it is internalized by a target cell or tissue. For transport to the endoplasmic reticulum (ER), for example, the compound can be conjugated to an ER transport peptide sequence. A number of such signal peptides are known in the art, including the signal peptide MMSFVSLLLVGILFYATEAEQLTKCEVFQ (SEQ ID NO: 4). Other suitable ER signal peptides include the N-terminus endoplasmic reticulum targeting sequence of the enzyme 17β-hydroxysteroid dehydrogenase type 11 (Horiguchi et al., “Identification and Characterization of the ER/Lipid Droplet-Targeting Sequence in 17β-hydroxysteroid Dehydrogenase Type 11 ,” Arch. Biochem. Biophys.  479(2):121-30 (2008), which is hereby incorporated by reference in its entirety), or any of the ER signaling peptides (including the nucleic acid sequences encoding the ER signal peptides) disclosed in U.S. Patent Application Publication No. 20080250515 to Reed et al., which is hereby incorporated by reference in its entirety. Additionally, the compound of the present invention can contain an ER retention signal, such as the retention signal KEDL (SEQ ID NO: 5). Methods of modifying the compounds of the present invention to incorporate transport peptides for localization of the compounds to the ER can be carried out as described in U.S. Patent Application Publication No. 20080250515 to Reed et al., which is hereby incorporated by reference in its entirety. 
     For transport to the nucleus, the compounds of the present invention can include a nuclear localization transport signal. Suitable nuclear transport peptide sequences are known in the art, including the nuclear transport peptide PPKKKRKV (SEQ ID NO: 6). Other nuclear localization transport signals include, for example, the nuclear localization sequence of acidic fibroblast growth factor and the nuclear localization sequence of the transcription factor NF-KB p50 as disclosed by U.S. Pat. No. 6,043,339 to Lin et al., which is hereby incorporated by reference in its entirety. Other nuclear localization peptide sequences known in the art are also suitable for use in the compounds of the present invention. 
     Suitable transport peptide sequences for targeting to the mitochondria include MLSLRQSIRFFKPATRTLCSSRYLL (SEQ ID NO: 7). Other suitable transport peptide sequences suitable for selectively targeting the compounds of the present invention to the mitochondria are disclosed in U.S. Patent Application Publication No. 20070161544 to Wipf, which is hereby incorporated by reference in its entirety. 
     The peptidomimetics of the present invention are designed to mimic a helix having the formula X 1 —X 2 —X 2 —X 3 —X 2 —X 2 —X 1 —X 4 —X 5 , wherein each X 1  is any negatively charged residue, each X 2  is any hydrophobic residue, X 3  is any positively-charged residue, X 4  is any polar residue, and X 5  is absent or any hydrophobic residue. In a preferred embodiment, the peptidomimetic mimics a helix having the formula X 1 —X 2 -L-X 3 —X 2 -L-X 1 —X 4 —X 5 . In a preferred embodiment, the peptidomimetic mimics a helix having the formula X 1 —X 2 -L-X 3 —X 2 -L-D-X 4 —X 5 . In a preferred embodiment, the peptidomimetic mimics a helix having the formula X 1 —X 2 -L-X 3 —X 2 -L-X 1 -Q-X 5 . In a preferred embodiment, the peptidomimetic mimics a helix having the formula X 1 —X 2 -L-X 3 —X 2 -L-D-Q-X 5  (SEQ ID NO: 8). In a preferred embodiment, the peptidomimetic mimics a helix having the formula XELA*RALDQ (SEQ ID NO: 9), where X is 4-pentenoic acid and A* is N-allylalanine. 
     As will be apparent to those of ordinary skill in the art, when R 2  and/or R 3  are a moiety of the recited formulae, the overall size of the compounds of Formula I, Formula II, and Formula III can be adjusted by varying the values of m′ and/or m″, which are independently zero or any number. Typically, m′ and m″ are independently from zero to about thirty (e.g., 0 to ˜18, 0 to ˜10, 0 to ˜5, ˜5 to ˜30, ˜5 to ˜18, ˜5 to ˜10, ˜8 to ˜30, ˜8 to ˜18, ˜8 to ˜10, ˜10 to ˜18, or ˜10 to ˜30). In one embodiment of compounds of Formula I, m′ and m″ are independently 4-10. In another embodiment of compounds of Formula I, m′ and m″ are independently 5-6. 
     As will be apparent to the skilled artisan, compounds of Formula I and Formula III include a diverse range of helical conformation, which depends on the values of m, n′, and n″. These helical conformations include 3 10 -helices (e.g., m=0 and n′+n″=2), α-helices (e.g., m=1 and n′+n″=2), π-helices (e.g., m=2 and n′+n″=2), and gramicidin helices (e.g., m=4 and n′+n″=2). In a preferred embodiment, the number of atoms in the backbone of the helical macrocycle is 12-15, more preferably 13 or 14. 
     In at least one embodiment of compounds of Formula I, m′″ is one and a is two. 
     In at least one embodiment, R 2  is: a beta amino acid, a moiety of Formula A where m′ is at least one and at least one b is two, a moiety of Formula A where c is two, or a moiety of Formula A where R 2′  is a beta amino acid. In at least one embodiment, R 3  is: a beta amino acid, a moiety of Formula B where m″ is at least one and at least one d is two, or a moiety of Formula B where R 3′  is a beta amino acid. Combinations of these embodiments are also contemplated. 
     When R 2  is a moiety of Formula A, m′ is preferably any number from one to 19. When R 3  is a moiety of Formula B, m″ is preferably any number from one to nine. 
     In preferred embodiments, the compound is a compound of Formula IA, Formula IIA, or Formula IIIA (i.e., a helix cyclized at the N-terminal); Formula IB, Formula IIB, or Formula IIIB (i.e., a helix cyclized mid-peptide); or Formula IC, Formula IIC, or Formula IIIC (i.e., a helix cyclized at the C-terminal): 
     
       
         
         
             
             
         
       
     
     where R 4  is independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, or an arylalkyl; 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     As will be apparent to the skilled artisan, the pattern of β substitution in the attached peptides of the peptidomimetics of Formulae I, II, and III can be controlled by adjusting the values for m′″ and a (when the peptidomimetic is a compound of Formula I), as well as m′, b, and c (when R 2  is a moiety of Formula A), and m″ and d (when R 3  is a moiety of Formula B). Substitution in peptidomimetics of Formulae IA, HA, IIIA, IB, IIB, IIIB, IC, IIC, and IIIC can further be controlled as will be apparent to the skilled artisan. In a preferred embodiment, the attached peptide has the formula α3/β1. Preferred peptidomimetics containing β-amino acid residues include those that mimic a helix having the formula X 1 -x 2 -X 2 —X 3 —X 2 —X 2 —X 1 —X 4 -x 5 , wherein X 5  is absent or any hydrophobic residue and the beta residues are shown in lower-case bold. Preferred embodiments include, without limitation, XeEGRaLDQ (SEQ ID NO: 10), XeLLRaLDQ (SEQ ID NO: 11), XeLARaLDQ (SEQ ID NO: 12), and XeEGRaLDQy (SEQ ID NO: 13). 
     The peptidomimetics of the present invention may be prepared using methods that are known in the art. By way of example, peptidomimetics of Formula I, which contain a hydrogen bond surrogate, may be prepared using the methods disclosed in, e.g., U.S. patent application Ser. No. 11/128,722, U.S. patent application Ser. No. 13/724,887, and Mahon &amp; Arora, “Design, Synthesis, and Protein-Targeting Properties of Thioether-Linked Hydrogen Bond Surrogate Helices,”  Chem. Commun . 48:1416-18 (2012), each of which is hereby incorporated by reference in its entirety. Peptidomimetics of Formula II, which contain a side-chain constraint, may be prepared using the methods disclosed in, e.g., Schafmeister et al.,  J. Am. Chem. Soc.  122:5891 (2000); Sawada &amp; Gellman,  J. Am. Chem. Soc.  133:7336 (2011); Patgiri et al.,  J. Am. Chem. Soc.  134:11495 (2012); Henchey et al.,  Curr. Opin. Chem. Biol.  12:692 (2008); Harrison et al.,  Proc. Nat&#39;l Acad. Sci. U.S.A.  107:11686 (2010); Shepherd et al.,  J. Am. Chem. Soc.  127:2974 (2005); Phelan et al.,  J. Am. Chem. Soc.  119:455 (1997); Jackson et al.,  J. Am. Chem. Soc.  113:9391 (1991); and Blackwell &amp; Grubbs,  Angew. Chem. Intl Ed. Engl.  37:3281 (1998), each of which is hereby incorporated by reference in its entirety. Peptidomimetics of Formula III, which contain both a hydrogen bond surrogate and a side-chain constraint, may be prepared using a combination of the above methods. 
     Another aspect of the present invention relates to pharmaceutical formulations comprising any of the above described peptidomimetics of Formula I, Formula II, or Formula III of the present invention (including the peptidomimetics of Formulae IA, IIA, IIIA, IB, IIB, IIIB, IC, IIC, and IIIC) and a pharmaceutically acceptable carrier. Acceptable pharmaceutical carriers include solutions, suspensions, emulsions, excipients, powders, or stabilizers. The carrier should be suitable for the desired mode of delivery. 
     In addition, the pharmaceutical formulations of the present invention may further comprise one or more pharmaceutically acceptable diluents, adjuvants, excipients, or vehicles, such as preserving agents, fillers, disintegrating agents, wetting agents, emulsifying agents, suspending agents, sweetening agents, flavoring agents, perfuming agents, antibacterial agents, antifungal agents, lubricating agents and dispensing agents, depending on the nature of the mode of administration and dosage forms. Examples of suspending agents include ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances. Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminum monosterate and gelatin. Examples of suitable carriers, diluents, solvents, or vehicles include water, ethanol, polyols, suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate. Examples of excipients include lactose, milk sugar, sodium citrate, calcium carbonate, and dicalcium phosphate. Examples of disintegrating agents include starch, alginic acids, and certain complex silicates. Examples of lubricants include magnesium stearate, sodium lauryl sulphate, talc, as well as high molecular weight polyethylene glycols. 
     The peptidomimetics and pharmaceutical formulations of the present invention may be used, inter alia, to inhibit the HIF-1α-p300/CBP interaction. 
     Another aspect of the present invention relates to a method of modulating transcription of a gene in a cell, wherein transcription of the gene is mediated by interaction of HIF-1α with CBP and/or p300. This method involves contacting the cell with a peptidomimetic of the present invention under conditions effective to modulate transcription of the gene. In a preferred embodiment, the cell is contacted under conditions effective to cause nuclear uptake of the peptide, where the peptide disrupts interaction of HIF-1α and p300/CBP and thereby reduces transcription of the gene. 
     Modulating according to this aspect of the present invention refers to up-regulating transcription or down-regulating transcription. 
     Genes whose transcription can be modulated according to this aspect of the present invention include ACADSB, ADM, AK4, ALDOC, ALG1, ANG, ANGPTL4, ANKRD37, ANKZF 1, ARHGAP28, ARID5A, ARNTL, ARRDC3, ASF1A, ASPM, AURKA, B4GALT4, BAMBI, BHLHE40, BHLHE41, BNIP3, BNIP3L, BOLA1, C1orf161, C1orf163, C3orf58, C4orf3, C7orf60, C7orf68, C8orf22, C8orf41, C14orf126, C17orf76, C18orf19, C1QL1, CA12, CA5B, CA9, CASZ1, CCDC80, CCNB1, CCNG2, CDC20, CDC23, CDCP1, CDK18, CDKN1A, CDKN3, CENPA, CENPE, CGGBP1, CHAC2, CNOT8, CPOX, CXCL16, CXCR4, DAPK1, DDX10, DEPDC1, DIS3L, DKFZp451A211, DLGAP5, DUSP5, DUSP5P, DUSP9, E2F5, EDN2, EFNA3, EGLN1, EGLN3, ELOVL6, ENO2, ERO1L, ERRFI1, FAM13A, FAM72A, FAM72B, FAM72C, FAM72D, FAM83D, FAM86B1, FAM86B2, FAM86C, FAM115C, FAM115C, FAM133A, FAM162A, FARSB, FBXO16, FBXO32, FBXO42, FERMT1, FLJ23867, FLJ35024, FLJ44715, FM, FOS, FOXD1, FUT11, FXYD3, FYN, G2E3, GBE1, GDF15, GEMIN5, GFPT2, GOLGA8A, GOLGA8B, GPATCH4, GPR146, GPR155, GPR160, GPRC5A, GPT2, GTF2IRD2, GTF2IRD2B, GYS1, H1F0, H2BFS, HAS2, HERC3, HEY1, HIST1H1C, HIST1H1E, HIST1H2AB, HIST1H2AC, HIST1H2AD, HIST1H2AE, HIST1H2AH, HIST1H2AI, HIST1H2AK, HIST1H2AL, HIST1H2BC, HIST1H2BE, HIST1H2BF, HIST1H2BG, HIST1H2BH, HIST1H2BI, HIST1H2BJ, HIST1H2BK, HIST1H2BM, HIST1H2BN, HIST1H3A, HIST1H3D, HIST1H3F, HIST1H3H, HIST1H4B, HIST1H4H, HIST1H4J, HIST1H4K, HIST2H2AA3, HIST2H2AA4, HIST2H2AB, HIST2H2AC, HIST2H2BA, HIST2H2BE, HIST2H2BF, HIST2H3A, HIST2H3C, HIST2H3D, HIST2H4A, HIST2H4B, HIST3H2A, HIVEP2, HK1, HK2, HMMR, HORMAD1, HOXD10, HPDL, HRH1, HSPA1A, HSPA1B, HYMAI, ID3, IDH2, IER3, IGFBP3, IGSF3, IL1RAP, IL2RG, ING2, INSIG1, INSIG2, IPMK, ITGA5, JUN, KAT2B, KCTD11, KDM3A, KIAA0586, KIAA1244, KIAA1432, KIAA1715, KIF14, KIF20A, KRT17, LOC154761, LOC645332, LOC653113, LOC100507405, LOX, LOXL2, LRP1, LST-3TM12, LTV1, MAFB, MAFK, MAK16, MAP2K1, MAP3K15, METTL7A, MLKL, MOBKL2A, MSTO1, MSTO2P, MUC1, MXI1, NAMPT, NARS2, NAV1, NDRG1, NDUFAF4, NEBL, NFIL3, NLN, NOG, NOL6, NOP2, NOP16, NOTCH3, NRG4, ORAI3, OSMR, OTUD1, P4HA1, P4HA2, PAG1, PAIP2B, PDHA1, PDK1, PDK3, PER1, PER2, PFKFB4, PFKP, PGM2L1, PIAS2, PLA2G4A, PLAGL1, PLIN2, PLK1, PLOD1, PLOD2, PMEPA1, PNO1, POLR1B, PPFIA4, PPL, PPP1R3B, PPP1R3C, PPP2R5B, PPRC1, PRELID2, PRMT3, PTGS2, PTTG1, PYGL, QSOX1, RAB20, RAB40C, RAB8B, RASSF2, RCOR2, RIOK3, RIT1, RLF, RNASE4, RNF 122, RNF24, RNU4-2, RORA, RPSA, RRAGD, RRS1, RUVBL1, SCARNA5, SCARNA6, SCFD2, SEC14L4, SEC61G, SERPINE1, SERPINI1, SERTAD2, SLC2A1, SLC2A3, SLC6A10P, SLC6A6, SLC6A8, SLC7A11, SLC27A2, SLCO1B3, SLCO4A1, SNAPC5, SNORA1, SNORA2A, SNORA6, SNORA13, SNORA42, SNORA60, SNORA62, SNORA74A, SNORA75, SNORD1A, SNORD14E, SNORD53, SNORD94, SNX33, SPAG4, SPICE1, SPINK5, SPRY1, STAMBPL1, STC2, SYT7, TAF9B, TBC1D30, TCP11L2, TET2, TGFB1, TMCO7, TMEM45A, TMEM45B, TMEM184A, TMOD1, TMPRSS3, TNFRSF 10D, TRIM59, TROAP, TSEN2, TSTD2, TTYH3, TWISTNB, UACA, UBASH3B, UFSP2, UPRT, UTP15, UTP20, VEGFA, VLDLR, VTRNA1-1, WDR3, WDR12, WDR35, WDR45L, WDR52, WSB1, XK, YEATS2, ZDBF2, ZNF 160, ZNF292, ZNF395, ZNF654, ZSWIM5, adenylate kinase 3, α 1B -adrenergic receptor, aldolase A, ceruloplasmin, c-Met protooncogene, CXCL12/SDF-1, endothelin-1, enolase 1, erythropoietin, glucose transporter 1, glucose transporter 3, glyceraldehyde-3-phosphate dehydrogenase, heme oxygenase 1, IGF binding protein 1, insulin-like growth factor 2, lactate dehydrogenase A, nitric oxide synthase 2, p35 srg , phosphoglycerate kinase 1, pyruvate kinase M, transferrin, tranferrin receptor, transforming growth factor β 3 , vascular endothelial growth factor, vascular endothelial growth factor receptor FLT-1, and vascular endothelial growth factor receptor KDR/Flk-1. Some uses for inhibiting transcription of some of these genes are shown in Table 1. Preferred genes include those identified in Table 5, infra. 
     
       
         
           
               
             
               
                 TABLE 1 
               
             
            
               
                   
               
               
                 Example Disorders 
               
            
           
           
               
               
            
               
                 Gene 
                 Treat/prevent 
               
               
                   
               
               
                 adrenomedullin 
                 Pheochromocytoma 
               
               
                 ceruloplasmin 
                 Lymphoma, acute and chronic 
               
               
                   
                 inflammation, 
               
               
                   
                 rheumatoid arthritis 
               
               
                 c-Met protooncogene 
                 Tumor Cells Invasion 
               
               
                 CXCL12/SDF-1 
                 Cancer Stem Cells Migration 
               
               
                 CXCR4 
                 Cancer Stem Cells Migration 
               
               
                 endothelin-1 
                 Abnormal vasoconstriction 
               
               
                 endothelin-2 
                 Abnormal vasoconstriction 
               
               
                 enolase 1 
                 Hashimoto&#39;s encephalopathy, 
               
               
                   
                 severe asthma 
               
               
                 erythropoietin 
                 Abnormal oxygen transport 
               
               
                 glucose transporter 1 
                 Aerobic glycolysis (Warburg effect) 
               
               
                 glucose transporter 3 
                 Aerobic glycolysis (Warburg effect) 
               
               
                 heme oxygenase 1 
                 Abnormal oxygen transport 
               
               
                 hexokinase 1 
                 Aerobic glycolysis (Warburg effect) 
               
               
                 hexokinase 2 
                 Aerobic glycolysis (Warburg effect) 
               
               
                 IGF binding protein 1 
                 Abnormal development and function of 
               
               
                   
                 organs (brain, liver) 
               
               
                 IGF binding protein 3 
                 Abnormal development and function of 
               
               
                   
                 organs (brain, liver) 
               
               
                 insulin-like growth factor 2 
                 Abnormal development and function of 
               
               
                   
                 organs (brain, liver) 
               
               
                 lactate dehydrogenase A 
                 Myocardial infarction 
               
               
                 lysyl oxidase 
                 Tumor Cells Invasion 
               
               
                 nitric oxide synthase 2 
                 Abnormal vasomotor tone 
               
               
                 tranferrin receptor 
                 Abnormal iron uptake/metabolism 
               
               
                 transferrin 
                 Abnormal iron uptake/metabolism 
               
               
                 vascular endothelial growth factor 
                 Angiogenesis (tumor, incl. cancer) 
               
               
                 vascular endothelial growth factor  
                 Angiogenesis (tumor, incl. cancer) 
               
               
                 receptor FLT-1 
                   
               
               
                 vascular endothelial growth factor  
                 Angiogenesis (tumor, incl. cancer) 
               
               
                 receptor KDR/Flk-1 
               
               
                   
               
            
           
         
       
     
     Yet another aspect of the present invention relates to a method of treating or preventing in a subject a disorder mediated by interaction of HIF-1α with CBP and/or p300. This method involves administering to the subject a peptidomimetic of the present invention under conditions effective to treat or prevent the disorder. 
     Disorders that can be treated or prevented include, for example, abnormal vasoconstriction, retinal ischemia (Zhu et al., “Long-Term Tolerance to Retinal Ischemia by Repetitive Hypoxic Preconditioning: Role of HIF-1α and Heme Oxygenase-1 ,” Invest. Ophthalmol. Vis. Sci.  48:1735-43 (2007); Ding et al., “Retinal Disease in Mice Lacking Hypoxia-Inducible Transcription Factor-2 α,” Invest. Ophthalmol. Vis. Sci.  46:1010-16 (2005), each of which is hereby incorporated by reference in its entirety), pulmonary hypertension (Simon et al., “Hypoxia-Induced Signaling in the Cardiovascular System,”  Annu. Rev. Physiol.  70:51-71 (2008); Eul et al., “Impact of HIF-1α and HIF-2α on Proliferation and Migration of Human Pulmonary Artery Fibroblasts in Hypoxia,”  FASEB J.  20:163-65 (2006), each of which is hereby incorporated by reference in its entirety), intrauterine growth retardation (Caramelo et al., “Respuesta a la Hipoxia. Un Mecanismo Sistémico Basado en el Control de la Expresión Génica [Response to Hypoxia. A Systemic Mechanism Based on the Control of Gene Expression],”  Medicina B. Aires  66:155-64 (2006); Tazuke et al., “Hypoxia Stimulates Insulin-Like Growth Factor Binding Protein 1 (IGFBP-1) Gene Expression in HepG2 Cells: A Possible Model for IGFBP-1 Expression in Fetal Hypoxia,”  Proc. Nat&#39;l Acad. Sci. USA  95:10188-93 (1998), each of which is hereby incorporated by reference in its entirety), diabetic retinopathy (Ritter et al., “Myeloid Progenitors Differentiate into Microglia and Promote Vascular Repair in a Model of Ischemic Retinopathy,”  J. Clin. Invest.  116:3266-76 (2006); Wilkinson-Berka et al., “The Role of Growth Hormone, Insulin-Like Growth Factor and Somatostatin in Diabetic Retinopathy,”  Curr. Med. Chem.  13:3307-17 (2006); Vinores et al., “Implication of the Hypoxia Response Element of the Vegf Promoter in Mouse Models of Retinal and Choroidal Neovascularization, but not Retinal Vascular Development,”  J. Cell. Physiol.  206:749-58 (2006); Caldwell et al., “Vascular Endothelial Growth Factor and Diabetic Retinopathy: Role of Oxidative Stress,”  Curr. Drug Targets  6:511-24 (2005), each of which is hereby incorporated by reference in its entirety), age-Related macular degeneration (Inoue et al., “Expression of Hypoxia-Inducible Factor 1α and 2α in Choroidal Neovascular Membranes Associated with Age-Related Macular Degeneration,”  Br. J. Ophthalmol . 91:1720-21 (2007); Zuluaga et al., “Synergies of VEGF Inhibition and Photodynamic Therapy in the Treatment of Age-Related Macular Degeneration,”  Invest. Ophthalmol. Vis. Sci.  48:1767-72 (2007); Provis, “Development of the Primate Retinal Vasculature,”  Prog. Retin. Eye Res.  20:799-821 (2001), each of which is hereby incorporated by reference in its entirety), diabetic macular edema (Vinores et al., “Implication of the Hypoxia Response Element of the Vegf Promoter in Mouse Models of Retinal and Choroidal Neovascularization, but not Retinal Vascular Development,”  J. Cell. Physiol.  206:749-58 (2006); Forooghian &amp; Das, “Anti-Angiogenic Effects of Ribonucleic Acid Interference Targeting Vascular Endothelial Growth Factor and Hypoxia-Inducible Factor-1 α,” Am. J. Ophthalmol.  144:761-68 (2007), each of which is hereby incorporated by reference in its entirety), and cancer (Marignol et al., “Hypoxia in Prostate Cancer: A Powerful Shield Against Tumour Destruction?”  Cancer Treat. Rev.  34:313-27 (2008); Galanis et al., “Reactive Oxygen Species and HIF-1 Signalling in Cancer,”  Cancer Lett.  266:12-20 (2008); Ushio-Fukai &amp; Nakamura, “Reactive Oxygen Species and Angiogenesis: NADPH Oxidase as Target for Cancer Therapy,”  Cancer Lett.  266:37-52 (2008); Adamski et al., “The Cellular Adaptations to Hypoxia as Novel Therapeutic Targets in Childhood Cancer,”  Cancer Treat. Rev.  34:231-46 (2008); Toffoli &amp; Michiels, “Intermittent Hypoxia Is a Key Regulator of Cancer Cell and Endothelial Cell Interplay in Tumours,”  FEBS J . 275:2991-3002 (2008), each of which is hereby incorporated by reference in its entirety). 
     The subject according to this aspect of the present invention is preferably a human subject. 
     The compounds of the present invention can be administered orally, parenterally, for example, subcutaneously, intravenously, intramuscularly, intraperitoneally, by intranasal instillation, or by application to mucous membranes, such as, that of the nose, throat, and bronchial tubes. They may be administered alone or with suitable pharmaceutical carriers, and can be in solid or liquid form such as, tablets, capsules, powders, solutions, suspensions, or emulsions. 
     The active compounds of the present invention may be orally administered, for example, with an inert diluent, or with an assimilable edible carrier, or they may be enclosed in hard or soft shell capsules, or they may be compressed into tablets, or they may be incorporated directly with the food of the diet. For oral therapeutic administration, these active compounds may be incorporated with excipients and used in the form of tablets, capsules, elixirs, suspensions, syrups, and the like. Such compositions and preparations should contain at least 0.1% of active compound. The percentage of the compound in these compositions may, of course, be varied and may conveniently be between about 2% to about 60% of the weight of the unit. The amount of active compound in such therapeutically useful compositions is such that a suitable dosage will be obtained. Preferred compositions according to the present invention are prepared so that an oral dosage unit contains between about 1 and 250 mg of active compound. 
     The tablets, capsules, and the like may also contain a binder such as gum tragacanth, acacia, corn starch, or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose, or saccharin. When the dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier, such as a fatty oil. 
     Various other materials may be present as coatings or to modify the physical form of the dosage unit. For instance, tablets may be coated with shellac, sugar, or both. A syrup may contain, in addition to active ingredient, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye, and flavoring such as cherry or orange flavor. 
     These active compounds may also be administered parenterally. Solutions or suspensions of these active compounds can be prepared in water suitably mixed with a surfactant, such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Illustrative oils are those of petroleum, animal, vegetable, or synthetic origin, for example, peanut oil, soybean oil, or mineral oil. In general, water, saline, aqueous dextrose and related sugar solution, and glycols such as, propylene glycol or polyethylene glycol, are preferred liquid carriers, particularly for injectable solutions. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms. 
     The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils. 
     The compounds of the present invention may also be administered directly to the airways in the form of an aerosol. For use as aerosols, the compounds of the present invention in solution or suspension may be packaged in a pressurized aerosol container together with suitable propellants, for example, hydrocarbon propellants like propane, butane, or isobutane with conventional adjuvants. The materials of the present invention also may be administered in a non-pressurized form such as in a nebulizer or atomizer. 
     Another aspect of the present invention relates to a method of reducing or preventing angiogenesis in a tissue. This method involves contacting the tissue with a peptidomimetic of the present invention under conditions effective to reduce or prevent angiogenesis in the tissue. 
     Preferred tissues according to this aspect of the present invention include tumors. 
     Yet another aspect of the present invention relates to a method of decreasing survival and/or proliferation of a cell under hypoxic conditions. This method involves contacting the cell with a peptidomimetic of the present invention under conditions effective to decrease survival and/or proliferation of the cell. 
     Suitable cells according to this and all aspects of the present invention include, without limitation, mammalian cells. Preferably, the cells are human cells. In at least one embodiment, the cells are cancer cells or are contained in the endothelial vasculature of a tissue that contains cancerous cells. Suitable cancer cells include, e.g., sarcoma cells, multiple myeloma cells, prostate cancer cells, melanoma cells, brain cancer cells, ovarian cancer cells, breast cancer cells, renal cancer cells, and eye cancer cells. 
     In all aspects of the present invention directed to methods involving contacting a cell with one or more peptidomimetics, contacting can be carried out using methods that will be apparent to the skilled artisan, and can be done in vitro or in vivo. 
     One approach for delivering agents into cells involves the use of liposomes. Basically, this involves providing a liposome which includes agent(s) to be delivered, and then contacting the target cell, tissue, or organ with the liposomes under conditions effective for delivery of the agent into the cell, tissue, or organ. 
     This liposome delivery system can also be made to accumulate at a target organ, tissue, or cell via active targeting (e.g., by incorporating an antibody or hormone on the surface of the liposomal vehicle). This can be achieved according to known methods. 
     An alternative approach for delivery of protein- or polypeptide-containing agents (e.g., peptidomimetics of the present invention containing one or more protein or polypeptide side chains) involves the conjugation of the desired agent to a polymer that is stabilized to avoid enzymatic degradation of the conjugated protein or polypeptide. Conjugated proteins or polypeptides of this type are described in U.S. Pat. No. 5,681,811 to Ekwuribe, which is hereby incorporated by reference in its entirety. 
     Yet another approach for delivery of agents involves preparation of chimeric agents according to U.S. Pat. No. 5,817,789 to Heartlein et al., which is hereby incorporated by reference in its entirety. The chimeric agent can include a ligand domain and the agent (e.g., a peptidomimetic of the invention). The ligand domain is specific for receptors located on a target cell. Thus, when the chimeric agent is delivered intravenously or otherwise introduced into blood or lymph, the chimeric agent will adsorb to the targeted cell, and the targeted cell will internalize the chimeric agent. 
     Peptidomimetics of the present invention may be delivered directly to the targeted cell/tissue/organ. 
     Additionally and/or alternatively, the peptidomimetics may be administered to a non-targeted area along with one or more agents that facilitate migration of the peptidomimetics to (and/or uptake by) a targeted tissue, organ, or cell. As will be apparent to one of ordinary skill in the art, the peptidomimetic itself can be modified to facilitate its transport to a target tissue, organ, or cell, including its transport across the blood-brain barrier; and/or to facilitate its uptake by a target cell (e.g., its transport across cell membranes). In a preferred embodiment, the peptide of the invention is modified, and/or delivered with an appropriate vehicle, to facilitate its delivery to the nucleus of the target cell (Wender et al., “The Design, Synthesis, and Evaluation of Molecules That Enable or Enhance Cellular Uptake: Peptoid Molecular Transporters,”  Proc. Nat&#39;l Acad. Sci. USA  97:13003-08 (2000); Roberts, “Buyer&#39;s Guide to Protein Transduction Reagents,”  Scientist  18:42-43 (2004); Joliot &amp; Prochiantz, “Transduction Peptides: From Technology to Physiology,”  Nat. Cell Biol . 6:189-96 (2004), each of which is hereby incorporated by reference in its entirety). Some example target cells, tissues, and/or organs for the embodiments described above are shown in Table 2. 
     
       
         
           
               
             
               
                 TABLE 2 
               
             
            
               
                   
               
               
                 Example Target Cells/Tissues/Organs 
               
            
           
           
               
               
            
               
                 Desired Effect 
                 Example Target(s) 
               
               
                   
               
               
                 Inhibit transcription of: 
                   
               
               
                 enolase 1 
                 Liver, brain, kidney, spleen, adipose,  
               
               
                   
                 lung 
               
               
                 glucose transporter 1 
                 Tumor, incl. cancer 
               
               
                 glucose transporter 3 
                 Tumor, incl. cancer 
               
               
                 hexokinase 1 
                 Tumor, incl. cancer 
               
               
                 hexokinase 2 
                 Tumor, incl. cancer 
               
               
                 insulin-like growth factor 2 
                 Brain, liver 
               
               
                 IGF binding protein 1 
                 Brain, liver 
               
               
                 IGF binding protein 3 
                 Brain, liver 
               
               
                 lactate dehydrogenase A 
                 Heart 
               
               
                 ceruloplasmin 
                 Lymphocytes/lymphatic tissue,  
               
               
                   
                 inflamed tissue, rheumatoid arthritic  
               
               
                   
                 tissue 
               
               
                 erythropoietin 
                 Liver, kidney 
               
               
                 transferrin 
                 Liver 
               
               
                 adrenomedullin 
                 Pheochromocytoma 
               
               
                 endothelin-1 
                 Endothelium 
               
               
                 nitric oxide synthase 2 
                 Vessels, cardiovascular cells/tissue 
               
               
                 vascular endothelial growth factor 
                 Tumor cells/tissue, incl. cancer 
               
               
                 vascular endothelial growth factor 
                 Tumor cells/tissue, incl. cancer 
               
               
                 receptor FLT-1 
                   
               
               
                 vascular endothelial growth factor 
                 Tumor cells/tissue, incl. cancer 
               
               
                 receptor KDR/Flk-1 
                   
               
            
           
           
               
            
               
                 Treat or prevent: 
               
            
           
           
               
               
            
               
                 retinal ischemia 
                 Retina (eye) 
               
               
                 pulmonary hypertension 
                 Lungs 
               
               
                 intrauterine growth retardation 
                 Uterus 
               
               
                 diabetic retinopathy 
                 Retina (eye) 
               
               
                 age-related macular degeneration 
                 Retina (eye) 
               
               
                 diabetic macular edema 
                 Retina (eye) 
               
               
                 Reduce or prevent angiogenesis 
                 Tumor cells/tissue, incl. cancer 
               
               
                 Decrease cell survival and/or  
                 Cancerous cells, cells contained in the  
               
               
                 proliferation 
                 endothelial vasculature of a tissue that  
               
               
                   
                 contains cancerous cells 
               
               
                   
               
            
           
         
       
     
     In vivo administration can be accomplished either via systemic administration to the subject or via targeted administration to affected tissues, organs, and/or cells, as described above. Typically, the therapeutic agent (i.e., a peptidomimetic of the present invention) will be administered to a patient in a vehicle that delivers the therapeutic agent(s) to the target cell, tissue, or organ. Typically, the therapeutic agent will be administered as a pharmaceutical formulation, such as those described above. 
     Exemplary routes of administration include, without limitation, orally, topically, transdermally, parenterally, subcutaneously, intravenously, intramuscularly, intraperitoneally, intraventricularly, and intralesionally; by intratracheal inoculation, aspiration, airway instillation, aerosolization, nebulization, intranasal instillation, oral or nasogastric instillation, intraperitoneal injection, intravascular injection, intravenous injection, intra-arterial injection (such as via the pulmonary artery), intramuscular injection, and intrapleural instillation; by application to mucous membranes (such as that of the nose, throat, bronchial tubes, genitals, and/or anus); and by implantation of a sustained release vehicle. 
     For use as aerosols, a peptidomimetic of the present invention in solution or suspension may be packaged in a pressurized aerosol container together with suitable propellants, for example, hydrocarbon propellants like propane, butane, or isobutane with conventional adjuvants. The peptidomimetics of the present invention also may be administered in a non-pressurized form. 
     Exemplary delivery devices include, without limitation, nebulizers, atomizers, liposomes (including both active and passive drug delivery techniques) (Wang &amp; Huang, “pH-Sensitive Immunoliposomes Mediate Target-Cell-Specific Delivery and Controlled Expression of a Foreign Gene in Mouse,” Proc. Nat&#39;l Acad. Sci. USA 84:7851-55 (1987); Bangham et al., “Diffusion of Univalent Ions Across the Lamellae of Swollen Phospholipids,”  J. Mol. Biol.  13:238-52 (1965); U.S. Pat. No. 5,653,996 to Hsu; U.S. Pat. No. 5,643,599 to Lee et al.; U.S. Pat. No. 5,885,613 to Holland et al.; U.S. Pat. No. 5,631,237 to Dzau &amp; Kaneda; U.S. Pat. No. 5,059,421 to Loughrey et al.; Wolff et al., “The Use of Monoclonal Anti-Thyl IgG1 for the Targeting of Liposomes to AKR-A Cells in Vitro and in Vivo,”  Biochim. Biophys. Acta  802:259-73 (1984), each of which is hereby incorporated by reference in its entirety), transdermal patches, implants, implantable or injectable protein depot compositions, and syringes. Other delivery systems which are known to those of skill in the art can also be employed to achieve the desired delivery of the peptidomimetic to the desired organ, tissue, or cells in vivo to effect this aspect of the present invention. 
     Contacting (including in vivo administration) can be carried out as frequently as required and for a duration that is suitable to provide the desired effect. For example, contacting can be carried out once or multiple times, and in vivo administration can be carried out with a single sustained-release dosage formulation or with multiple (e.g., daily) doses. 
     The amount to be administered will, of course, vary depending upon the particular conditions and treatment regimen. The amount/dose required to obtain the desired effect may vary depending on the agent, formulation, cell type, culture conditions (for ex vivo embodiments), the duration for which treatment is desired, and, for in vivo embodiments, the individual to whom the agent is administered. 
     Effective amounts can be determined empirically by those of skill in the art. For example, this may involve assays in which varying amounts of the peptidomimetic of the invention are administered to cells in culture and the concentration effective for obtaining the desired result is calculated. Determination of effective amounts for in vivo administration may also involve in vitro assays in which varying doses of agent are administered to cells in culture and the concentration of agent effective for achieving the desired result is determined in order to calculate the concentration required in vivo. Effective amounts may also be based on in vivo animal studies. 
     Another aspect of the present invention relates to a method of identifying an agent that potentially inhibits interaction of HIF-1α with CBP and/or p300. This method involves providing a peptidomimetic of the present invention, contacting the peptidomimetic with a test agent, and detecting whether the test agent selectively binds to the peptidomimetic, wherein a test agent that selectively binds to the peptidomimetic is identified as a potential inhibitor of interaction between HIF-1α with CBP and/or p300. 
     This aspect of the present invention can be carried out in a variety of ways, that will be apparent to the skilled artisan. For example, the affinity of the test agent for the peptidomimetic of the present invention may be measured using isothermal titration calorimetry analysis (Wiseman et al., “Rapid Measurement of Binding Constants and Heats of Binding Using a New Titration calorimeter,”  Anal. Biochem.  179:131-37 (1989); Freire et al., “Isothermal Titration calorimetry,”  Anal. Chem.  62:A950-A959 (1990); Chervenak &amp; Toone, “Calorimetric Analysis of the Binding of Lectins with Overlapping Carbohydrate-Binding Ligand Specificities,” Biochemistry 34:5685-95 (1995); Aki et al., “Competitive Binding of Drugs to the Multiple Binding Sites on Human Serum Albumin. A calorimetric Study,”  J. Thermal Anal. Calorim.  57:361-70 (1999); Graziano et al., “Linkage of Proton Binding to the Thermal Unfolding of Sso7d from the Hyperthermophilic Archaebacterium  Sulfolobus solfataricus,” Int&#39; J. Biol. Macromolecules  26:45-53 (1999); Pluschke &amp; Mutz, “Use of Isothermal Titration calorimetry in the Development of Molecularly Defined Vaccines,”  J. Thermal Anal. Calorim.  57:377-88 (1999); Corbell et al., “A Comparison of Biological and calorimetric Analyses of Multivalent Glycodendrimer Ligands for Concanavalin A,”  Tetrahedron - Asymmetry  11:95-111 (2000), which are hereby incorporated by reference in their entirety). In one embodiment, a test agent is identified as a potential inhibitor of interaction between HIF-1α with CBP and/or p300 if the dissociation constant (K d ) for the test agent and the peptidomimetic of the invention is 50 μM or less. In another embodiment, the K d  is 200 nM or less. In another embodiment, the K d  is 100 nM or less. 
     Test agents identified as potential inhibitors of HIF-1α-p300/CREB interaction may be subjected to further testing to confirm their ability to inhibit interaction between HIF-1α with CBP and/or p300. 
     The present invention may be further illustrated by reference to the following examples. 
     EXAMPLES 
     The following Examples are intended to illustrate, but by no means are intended to limit, the scope of the present invention as set forth in the appended claims. 
     Example 1 
     General Materials and Methods 
     Commercial grade solvents and reagents were used without further purification. Fmoc amino acids and peptide synthesis reagents were purchased from Novabiochem. Hoveyda-Grubbs (second-generation) catalyst was obtained from Sigma. Molecular biology grade salts and buffers were obtained from Sigma. Cell culture media and reagents were purchased from Invitrogen, unless otherwise stated. 
     Peptide Synthesis 
     Peptides were synthesized on a CEM Liberty series microwave peptide synthesizer and purified by reversed-phase HPLC. The identity and purity of the peptides were confirmed by LCMS (see Table 3 below). 
     
       
         
           
               
             
               
                 TABLE 3 
               
             
            
               
                   
               
               
                 Mass Spectroscopic Characterization of 
               
               
                 HBS Helices and Peptide 3 
               
            
           
           
               
               
               
               
            
               
                   
                   
                 Calculated 
                 Observed 
               
               
                 Compound 
                 Sequence a   
                 [M + H] +   
                 [M + H] +   
               
               
                   
               
               
                 HBS 1 
                 XELA*RALDQ-NH 2   
                 1008.5 
                 1008.5 
               
               
                   
                 (SEQ ID NO: 14) 
                   
                   
               
               
                   
               
               
                 HBS 2 
                 XELA*RAADQ-NH 2   
                  966.5 
                  966.5 
               
               
                   
                 (SEQ ID NO: 15) 
                   
                   
               
               
                   
               
               
                 Peptide 3 
                 AcELARALDQ-NH 2   
                  956.5 
                  956.5 
               
               
                   
                 (SEQ ID NO: 16) 
               
               
                   
               
               
                   a X denotes 4-pentenoic acid; A* = N-allylalanine. 
               
            
           
         
       
     
     Synthesis of HBS Peptides 
     HBS helices containing only α-amino acid residues were synthesized as previously described (Patgiri et al., “Solid-Phase Synthesis of Short α-Helices Stabilized by the Hydrogen Bond Surrogate Approach,”  Nat. Protoc.  5(10):1857-65 (2010), which is hereby incorporated by reference in its entirety) (see Scheme 1 below). 
     
       
         
         
             
             
         
       
     
     Peptide sequences up to the i+3 rd  residue of the putative helix (4 in Scheme 1) were synthesized on solid phase on a CEM Liberty Series microwave peptide synthesizer. A solution containing premixed o-nitrobenzesulfonyl chloride (10 eq) and 2,4,6-collidine (10 eq) in DCM was added to Fmoc-deprotected, resin bound 4. Resin was washed sequentially with DCM (×3), DMF (×3), DCM (×3), and diethyl ether. Resin was dried overnight under vacuum. Dried resin, PPh 3 , and Pd 2 (dba) 3  were flushed with argon for 30 minutes. Upon addition of THF, allymethylcarbonate was added to the reaction vessel containing dissolved reactants and resin. The solution was agitated at room temperature for 3 to 5 hours under argon to afford 5. 
     Resin was filtered and washed with DCM (×3), DMF (×3), 0.2 M sodium diethylcarbamate trihydrate in NMP, and diethyl ether. The nosyl protecting group was then removed by the addition of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 5eq) and 2-mercaptoethanol (10 eq.) in DMF. Resin was washed with DMF (×3), DCM (×3), and diethyl ether and treated with the desired Fmoc amino acid (20 eq.), DIC (20 eq.), and HOAt (10 eq.) in DMF and was allowed to agitate at room temperature for 12 to 16 hours. 
     Resin containing 8 was then washed with DMF (×3), DCM (×3), and DMF (×3), and coupled to the desired Fmoc amino acid residue (5 eq.) and 4-pentenoic acid (5 eq.) with HBTU (5 eq.) and DIEA (10 eq.) in DMF. 
     Ring-closing metathesis of bis-olefin 9 was performed with Hoveyda-Grubbs II catalyst (20 mol %) in 1,2-dichloroethane under microwave irradiation at 120° C. for 10 minutes as described in Patgiri et al., “Solid-Phase Synthesis of Short α-Helices Stabilized by the Hydrogen Bond Surrogate Approach,”  Nat. Protoc . 5(10):1857-65 (2010); Chapman &amp; Arora, “Optimized Synthesis of Hydrogen-Bond Surrogate Helices: Surprising Effects of Microwave Heating on the Activity of Grubbs Catalysts,”  Org. Lett.  8(25):5825-28 (2006); and Patgiri et al., “Solid Phase Synthesis of Hydrogen Bond Surrogate Derived Alpha-Helices: Resolving the Case of a Difficult Amide Coupling,”  Org. Biomol. Chem.  8:1773-76 (2010), each of which is hereby incorporated by reference in its entirety. Peptides were cleaved from the resin using TFA:TIS:water (95:2.5:2.5), and purified by reversed-phase HPLC (C 18  column) in 0.1% TFA acetonitrile/water gradients and characterized by ESI-MS. The computational alanine scanning mutagenesis energies calculated with Rosetta ver. 3.3. are shown in Table 4 below. Scans were performed on the HIF-1α/CBP complex (PDB codes 1L8C and 1L3E). Peptides were also analyzed by HPLC (see  FIGS. 4A-C ). 
     
       
         
           
               
             
               
                 TABLE 4 
               
             
            
               
                   
               
               
                 Computational Alanine Scanning Mutagenesis Energies 
               
               
                 HELIX B (817-824): ELLRALDQ (SEQ ID NO: 17) 
               
            
           
           
               
               
               
            
               
                 Residue 
                 Helix B residue 
                 ΔΔG (kcal/mol) 
               
               
                   
               
            
           
           
               
               
               
            
               
                 Leu 
                 818 
                 1.4 
               
               
                 Leu 
                 819 
                 0.5 
               
               
                 Arg 
                 820 
                 0.1 
               
               
                 Ala 
                 821 
                 0.0 
               
               
                 Leu 
                 82 
                 21.9 
               
               
                 Asp 
                 823 
                 1.4 
               
               
                 Gln 
                 824 
                 0.3 
               
               
                   
               
            
           
         
       
     
     An HBS helix containing β-amino acid residues (i.e., XeEG*RaLDQ-NH 2  (SEQ ID NO: 18), bold lower case letters denote β-residues) was synthesized as previously described with the necessary modification (Patgiri et al., “Solid-Phase Synthesis of Short α-Helices Stabilized by the Hydrogen Bond Surrogate Approach,”  Nat. Protoc.  5(10):1857-65 (2010); Patgiri et al., “Nucleation Effects in Peptide Foldamers,”  J. Am. Chem. Soc.  134(28):11495-502 (2012), each of which is hereby incorporated by reference in its entirety) (see Scheme 2 below). 
     
       
         
         
             
             
         
       
     
     The peptide sequence up to the putative helix 10 in Scheme 2 was synthesized on solid phase via a CEM Liberty Series microwave peptide synthesizer or by hand. A solution containing premixed β-Fmoc amino acid (20 eq.), DIC (20 eq.), and HOAt (10 eq.) in DMF was added to Fmoc-deprotected resin bound 10 at room temperature for 12 to 16 hours. Resin was washed sequentially with DCM (×3), DMF (×3), and MeOH (×3) to afford 11. 
     After Fmoc-deprotection and two further α-amino acid peptide elongation, a solution containing premixed o-nitrobenzesulfonyl chloride (10 eq) and 2,4,6-collidine (10 eq) in DCM was added to Fmoc-deprotected, resin bound 11. Resin was washed sequentially with DCM (×3), DMF (×3), DCM (×3), and diethyl ether to afford 12. 
     Resin bound 12 was dried overnight under vacuum, then PPh 3 , and Pd 2 (dba) 3  were added and flushed with argon for 30 minutes. Upon addition of THF, allymethylcarbonate was added to the reaction vessel containing dissolved reactants and resin. The solution was agitated at room temperature for 3 to 5 hours under argon to afford 13. 
     Resin was filtered and washed with DCM (×3), DMF (×3), 0.2 M sodium diethylcarbamate trihydrate in NMP, and diethyl ether. The nosyl protecting group was then removed by the addition of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 5eq) and 2-mercaptoethanol (10 eq.) in DMF. Resin was washed with DMF (×3), DCM (×3), and diethyl ether and treated with the desired Fmoc amino acid (20 eq.), DIC (20 eq.), and HOAt (10 eq.) in DMF and was allowed to agitate at room temperature for 12 to 16 hours. 
     Resin containing 14 was then washed with DMF (×3), DCM (×3), and MeOH (×3), and coupled to the desired β-Fmoc amino acid residue (5 eq.). Use of 4-pentenoic acid (5 eq.) DIC (20 eq.), and HOAt (10 eq.) in DMF afforded 15. 
     Ring-closing metathesis of bis-olefin 15 was performed with Hoveyda-Grubbs II catalyst (20 mol %) in 1,2-dichloroethane under microwave irradiation at 120° C. for 10 minutes as described in Patgiri et al., “Solid-Phase Synthesis of Short α-Helices Stabilized by the Hydrogen Bond Surrogate Approach,”  Nat. Protoc . 5(10):1857-65 (2010); Patgiri et al., “Nucleation Effects in Peptide Foldamers,”  J. Am. Chem. Soc.  134(28):11495-502 (2012); Chapman &amp; Arora, “Optimized Synthesis of Hydrogen-Bond Surrogate Helices: Surprising Effects of Microwave Heating on the Activity of Grubbs Catalysts,”  Org. Lett.  8(25):5825-28 (2006); and Patgiri et al., “Solid Phase Synthesis of Hydrogen Bond Surrogate Derived Alpha-Helices: Resolving the Case of a Difficult Amide Coupling,”  Org. Biomol. Chem . 8:1773-76 (2010), each of which is hereby incorporated by reference in its entirety. Peptides were cleaved from the resin using TFA:TIS:water (95:2.5:2.5), and purified by reversed-phase HPLC (C 18  column) in 0.1% TFA acetonitrile/water gradients and characterized by ESI-MS. 
     Additional mimics containing beta amino acids, including XeLL*RaLDQ-NH 2  (SEQ ID NO: 19), XeLA*RaLDQ-NH 2  (SEQ ID NO: 20), XeEG*RaLDQy-NH 2  (SEQ ID NO: 21), will also be synthesized. The β-residue-containing mimics are expected to be more resistant to degradation than their α-amino acid counterparts. 
     Circular Dichroism Studies 
     CD spectra were recorded on an AVIV 202SF CD spectrometer equipped with a temperature controller using 1 mm length cells and a scan speed of 0.5 nm/min at 298K. The spectra were averaged over 10 scans with the baseline subtracted from analogous conditions as those for the samples. The samples were prepared in 10 mM. KF with the final peptide concentration of 50 μM. 
     Plasmids 
     The DNA sequence of human p300 CH1 domain (amino acid residues 323-423) was designed as an insert and subcloned into a pUC57 plasmid by Genscript, Inc. After transformation of the plasmid in JM109 bacteria (Promega), the gene sequence was subcloned into BamHI and EcoRI restriction sites of pGEX-4T-2 expression vector (Amersham). 
     Cloning and Expression of  15 N p300-CH1 
     The pGEX 4T-2-p300 fusion vector was transformed into BL21 (DE3)-competent  E. coli  (Novagen) in M9 minimal media with  15 NH 4 Cl as the main nitrogen source. Protein production was induced with 1 mM IPTG at O.D. 600 of 1 for 16 hours at 15° C. Production of the desired p300-CH1-GST fusion product was verified by SDS-PAGE. Bacteria were harvested and resuspended in the lysis buffer with 20 mM Phosphate buffer (Research Products International, Corp.), 100 μM DTT (Fisher), 100 μM ZnSO 4  (Sigma), 0.5% TritonX 100 (Sigma), 1 mg/mL Pepstatin A (Research Products International, Corp.), 10 mg/mL Leupeptin A (Research Products International, Corp.), 500 μM PMSF (Sigma), and 0.5% glycerol at pH 8.0. Pellets were lysed by sonication and centrifuged at 4° C., 20,000 rpm, for 20 minutes. Fusion protein was collected from the bacterial supernatant and purified by affinity chromatography using glutathione Sepharose 4B beads (Amersham) prepared according to the manufacturer&#39;s directions. GST-tag was cleaved by thrombin and protein was eluted from resin. Collected fractions were assayed by SDS-PAGE gel; pooled fractions were treated with protease inhibitor cocktail (Sigma) and against a buffer containing 10 mM Tris, 50 mM NaCl, 2 mM DTT (Fisher), and 3 equivalents ZnSO 4  at pH 8.0 to ensure proper folding (vide supra). 
     Tryptophan Fluorescence Binding Assay 
     Spectra were recorded on a QuantaMaster 40 spectrofluorometer (Photon Technology International) in a 10 mm quartz fluorometer cell at 25° C. with 4 nm excitation and 4 nm emission slit widths from 200 to 400 nm at intervals of 1 nm/s. Samples were excited at 295 nm and fluorescence emission was measured from 200-400 nm and recorded at 335 nm. Peptide stock solutions were prepared in DMSO. Aliquots containing 1 μL DMSO stocks were added to 400 μL of 1 μM p300-CH1 in 50 mM Tris and 100 mM NaCl (pH 8.0). After each addition, the sample was allowed to equilibrate for 5 minutes before UV analysis. Background absorbance and sample dilution effects were corrected by titrating DMSO into p300-CH1 in an analogous manner. Final fluorescence is reported as the absolute value of [(F 1 −F 0 )/F 1 ]*100, where F 1  is the final fluorescence upon titration and F 0  is the fluorescence of the blank DMSO titration. EC 50  values for each peptide were determined by fitting the experimental data to a sigmoidal dose-response nonlinear regression model on GraphPad Prism 5.0, and the dissociation constants, K D , were obtained from equation (1) 
         K   D =( EC   50 ×(1− F )+ P×F   2 )/ F−P   (1)
         P=Total concentration of protein   F=Fraction of bound peptide=0.5       

     Fluorescence Polarization Assay 
     The relative affinity of peptides for  15 N-labeled p300-CH1 was determined using fluorescence polarization binding assay with fluoresceine-tagged HIF-1αC-TAD 786-826 . The polarization experiments were performed with a DTX 880 Multimode Detector (Beckman) at 25° C., with excitation and emission wavelengths of 485 and 525 nm, respectively. Addition of an increasing concentration (0 nm to 13.5 μM) of p300-CH1 protein to a 15 nM solution of fluorescein labeled HIF peptide in 20 mM Tris pH 8.0, 50 mM NaCl, 2 mM DTT, 3 eq ZnSO 4 , and 0.1% pluronic F-68 (Sigma) in 96 well plates afforded the IC 50  value, which was fit into equation (2) to calculate the dissociation constant (K D ) for the HIF/p300 complex (Roehrl et al., “A General Framework for Development and Data Analysis of Competitive High-Throughput Screens for Small-Molecule Inhibitors of Protein-Protein Interactions by Fluorescence Polarization,” Biochemistry 43(51):16056-66 (2004), which is hereby incorporated by reference in its entirety). 
         K   D =( R   T ×(1− F   SB )+ L   ST   ×F   SB   2 )/ F   SB   −L   ST   (2)
         R T =Total concentration of p300-CH1 protein   L ST =Total concentration of fluorescent peptide   F SB =Fraction of bound fluorescent peptide       

     The binding affinity (K D ) reported for each peptide is the average of three individual experiments, and was determined by fitting the experimental data to a sigmoidal dose-response nonlinear regression model on GraphPad Prism 5.0. The K D  of Flu-HIF C-TAD was determined to be 31±3 nM. For competitive inhibition experiments, a solution of 300 nM p300-CH1 and 15 nM Flu-HIF C-TAD in buffer (20 mM Tris (pH 8.0), 50 mM NaCl, 2 mM DTT, and 150 μM ZnSO 4 ) and 0.1% pluronic acid was incubated at 25° C. in a 96 well plate. After 30 minutes, appropriate concentrations of the HBS or linear peptides were added to the p300-CH1/Flu-HIF C-TAD solution and the resulting mixtures were incubated at 25° C. for 30 minutes before measuring the degree of dissociation of Flu-HIF C-TAD by polarization. The EC 50  was fit into equation (3) to calculate the K, value of HBS 1. The inhibition curve is shown in  FIG. 5C . 
         K   i   =K   D1   *F   SB *(( L   T   /L   ST   *F   SB2 −( K   D1   +L   ST   +R   T )* F   SB   +R   T ))−1/(1− F   SB ))  (3)
         K D =K D  of fluorescent probe Flu-HIF C-TAD   R T =Total concentration of p300-CH1 protein   L ST =Total concentration of HIF fluorescent peptide   F SB =Fraction of bound HBS 1 (at EC 50 )   L T =Total concentration of HBS 1 (EC 50 )       

       1 H- 15 N HSQC NMR Spectroscopy 
     Protein samples were prepared as described above. Uniformly  15 N-labelled p300-CH1 was concentrated to 69 μM in NMR buffer (10 mM Tris pH 8, 50 mM NaCl, 2 mM DTT, and 207 μM ZnSO 4 ) using a 3 kDa MWCO Amicon Ultra centrifugal filter (Millipore) and supplemented with 5% D 2 O. For HSQC titration experiments, data was collected on a 600 MHz Bruker four-channel NMR system at 25° C. and analyzed with the TopSpin software (Bruker). For Zn 2+  experiments, data were collected on Agilent 600 MHz at 25° C. and analyzed using Sparky3 (Univ. of California). 
     For the HSQC titration experiments, five and ten molar equivalents of HBS 1 in DMSO were added to  15 N-labelled p300-CH1, and the data were collected as described above. Mean chemical shift difference (Δδ NH ) observed for  1 H and  15 N nuclei of various resonances were calculated as described in Williamson, “Using Chemical Shift Perturbation to Characterise Ligand Binding,”  Prog. Nucl. Mag. Resonance Spectr.  73(0):1-16 (2013), which is hereby incorporated by reference in its entirety, where a is the range of H ppm shifts divided by the range of NH ppm shifts (α=⅛). 
         d=√ {square root over (1/2[δ H   2 +(α·δ N   2 )])}
 
     Cell Lines and Cell Culture 
     Human cervical epithelial adenocarcinoma (HeLa) and human renal cell carcinoma (786-0) cell lines were obtained from ATCC. Aggressive human breast carcinoma stably transfected with an HRE luciferase construct (MDA-MB-231-HRE-Luc) was a gift of Dr. Robert Gillies. HeLa cells were grown at 37° C. in a humidified atmosphere with 5% CO 2  in high glucose Dulbecco&#39;s Modified Eagle&#39;s Medium (DMEM, Sigma) supplemented with 10%, 2%, or 02% of fetal bovine serum (FBS, Irvine Scientific) and 0.5% Pen-Strep (Sigma). MDA-MB-231-HRE-Luc cells were grown in high glucose DMEM supplemented with 10% fetal bovine serum and 0.4 g/L geneticin (RPI). Hypoxia was mimicked with desferrioxamine mesylate (DFO, Sigma) at a concentration of 300 μM or by GasPak EZ pouch (BD Biosciences). Cell growth and morphology were monitored by phase-contrast microscopy. 
     Isolation of mRNA 
     HeLa cells (˜70% confluent) were plated in 6-well dishes (BD Falcon) at a density of 1.5×10 5  cells/mL. After attachment, cells were treated with 1.5 mL of fresh media containing HBS 1, HBS 2, and peptide 1 at concentrations of 10 μM and 50 μM. All samples, including vehicle, contained a final concentration of 0.1% DMSO. After 6 hours, hypoxia was induced with DFO (300 μM) or GasPak EZ pouch and cells were incubated for another 18 and 42 hours, respectively. Cells were lysed and RNA isolated according to the protocol described in Dubey et al., “Suppression of Tumor Growth by Designed Dimeric Epidithiodiketopiperazine Targeting Hypoxia-Inducible Transcription Factor Complex,”  J. Am. Chem. Soc . 135(11):4537-49 (2013), which is hereby incorporated by reference in its entirety. 
     Analysis of Gene Expression 
     Real-time qRT-PCR was used to determine the effect of HBS 1, HBS 2, and peptide 1 on VEGF, LOX, and SLC2A1 (GLUT1) genes in the HeLa cell lines, as described in Dubey et al., “Suppression of Tumor Growth by Designed Dimeric Epidithiodiketopiperazine Targeting Hypoxia-Inducible Transcription Factor Complex,”  J. Am. Chem. Soc.  135(11):4537-49 (2013), which is hereby incorporated by reference in its entirety. Statistical analyses were performed with data from four independent replicates. 
     Cell Viability Assays 
     HeLa cells were plated in a 96-well plate at a density of 6,000 cells/well and allowed to form a monolayer before adding the compounds. After attachment, the media was replaced by 100 μL of fresh media containing HBS 1, HBS 2, or peptide 1 at a concentration ranging from 1 μM to 100 μM, and 0.1% DMSO as a vehicle. After 24 hours of incubation with compounds, 11 μL of 3-(4,5 -dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide (MTT, Sigma) at a concentration of 5 mg/mL in PBS was added to each well and incubated at 37° C. and 5% CO 2  for an additional 3 hours. After 3 hours of incubation, the media was removed and purple crystals were dissolved in 100 μL of dimethyl sulfoxide (DMSO). The absorbance was measured at 570 nm with a correction at 690 nm in order to quantify the amount of formed purple formazan. All experiments were performed in quadruplicate. 
     Luciferase Assays 
     MDA-MB-231-HRE-Luc cells were plated in 24-well plates (BD Falcon) at a seeding density of 35,000 cells/mL. Cells were allowed to adhere and form a monolayer before adding the compounds (˜70% confluence). After attachment, cells were treated with 1 mL of fresh media containing HBS 1, HBS 2, or peptide 1 at a concentration of 10 μM and 50 μM. All samples contained a final concentration of 0.1% DMSO; vehicle samples were treated with cell culture media containing 0.1% DMSO. Cells were incubated for 6 hours at 37° C. and 5% CO 2  and then hypoxia was induced by placing the cells into GasPak EZ pouch for another 18 hours. The lysates were isolated by using cell culture lysis reagent (Promega). Prior to collecting cell lysate, halt protease inhibitor cocktail (Thermo Scientific) was added to the cell culture lysis reagent in order to ensure the stability of proteins. Cell lysates were collected into low-adhesion pre-chilled Eppendorf tubes (USA Scientific) and centrifuged at 13,000 rpm for 5 minutes at 4° C. Supernatant was collected into another set of pre-chilled Eppendorf tubes and the pellet was discarded. Luciferase assay reagent (100 μL, Promega) was added to 20 μL of cell lysate and luminescence intensity was measured by Turner TD-20e luminometer. The results were normalized to total protein concentration determined by BCA assay. Briefly, 10 μL of cell lysate was added to 200 μL of BCA reagent. Absorbance was measured at 562 nm using a BioTek Synergy 2 microplate reader and normalized to BSA solutions at a concentration range of 125 μg/mL to 2000 μg/mL as standards. 
     Determination of Protein Levels with ELISA 
     Cells were plated in 24-well dishes (BD-Falcon) at a density of 35,000 cells/mL. Cells were allowed to attach overnight (˜70% confluent) before dosing with the compound. After 24 hours, the old media was replaced with fresh media containing 2% FBS, and HBS 1 at concentrations ranging from 1 μM to 10 μM. All samples contained a final concentration of 0.1% DMSO; vehicle samples were treated with cell culture media containing 0.1% DMSO. Cells were incubated tier 6 hours at 37° C. and 5% CO 2  and hypoxia was induced with DFO (300 μM), and cells were incubated for another 18 hours. The supernatant was collected and the levels of VEGF were measured with the Human Quantikine VEGF kit (R&amp;D Systems) in accordance with the manufacturer&#39;s protocol. Absorbance was measured at 450 nm on a BioTek Synergy 2 microplate reader. The readings were normalized to a total protein concentration. Every experiment was performed in quadruplicate. 
     Western Blot Analysis of HIF-1α Levels 
     HeLa cells were plated in a 75 cm 2  culture flask and allowed to reach 70% confluence. Cells were treated with vehicle or HBS 1 at 10 μM concentration in the cell culture media containing 10% FBS. AU samples contained a final concentration of 0.1% DMSO. Cells were incubated for 6 hours and hypoxia was induced with 300 μM. DFO. After incubation for an additional 18 hours, cells were lysed and cytoplasmic and nuclear extracts were collected using a NE-PER kit (Pierce) according to the manufacturer&#39;s protocol and blotted as described in Dubey et al., “Suppression of Tumor Growth by Designed Dimeric Epidithiodiketopiperazine Targeting Hypoxia-Inducible Transcription Factor Complex,”  J. Am. Chem. Soc . 135(11):4537-49 (2013), which is hereby incorporated by reference in its entirety. 
     Plasma Stability and Biodistribution Studies 
     Plasma stability and biodistribution studies were performed in 10-week-old female BALB/c mice (Charles River) with 3 mice per time point. Briefly, HBS 1 or peptide 3 was dissolved in 70 μL of sterile PBS and administered intravenously at a dose of 1 mg/kg. Then, 1 mL of blood was collected by cardiac puncture at euthanasia at the following time points: 30 min., 1 h., 2 h., 4 h., 6 h., 8 h., 12 h., 16 h., and 24 h. after drug administration. The experiments were performed under an approved IACUC protocol at the University of Southern California. 
     Samples were prepared by mixing 30 μL of plasma with 20 μL of 50% MeOH and 50% aqueous 1% formic acid. The mixture was vortexed and mixed with an additional 120 μL of 0.5% formic acid in MeOH/ACN (4:6) and 20 μL of 2.0 μg/mL isoproterenol in MeOH/1% aqueous formic acid (1:1) as an internal standard. The mixture was vortexed again for 2 minutes and centrifuged at 13,000 rpm for 4 minutes. Next, 20 μL of the supernatant was transferred to a new tube and mixed with 180 μL of 50% MeOH/ACN (4:6) and 50% aqueous 1% formic acid. Standard curves were prepared by mixing the plasma from three untreated mice with 20 μL of 50% MeOH and 50% aqueous 1% formic acid prepared with HBS 1 or peptide 3 at a concentration range of 0.05-2 μg/mL. The standard curves, as determined by linear regression, displayed good linearity (r 2 &gt;0.98) over the range tested. 
     Samples were analyzed by LC/MS/MS using an Agilent 6210 time-of-flight LC/MS system. HPLC separation was achieved using a Prevail 3u C 18  100×2.1 mm column (Grace Davison, Deerfield, Ill., USA). The column temperature was maintained at 20° C. The mobile phase consisted of A (5% acetonitrile and 95% of 0.05% aqueous formic acid) and B (5% of 05% aqueous formic acid and 95% acetonitrile). The following gradient program was used: 0% B (0 min, 0.125 ml/min), 100% B (17 min, 0.125 ml/min). The total run time was 35 minutes. The electrospray ionization source of the mass spectrometer was operated in positive ion mode with the capillary voltage set to 4 kV, and the cone and collision cell voltages optimized to 60 and 170 V. The source temperature was 120° C. and the desolvation temperature was 300° C. A solvent delay/divert program was used from 0 to 4.0 minutes to minimize the mobile phase to flow to the source. Agilent MassHunter Workstation version B.02.01 software was used for data acquisition and processing. 
     Gene Expression Profiling 
     Experiments were carried out with HeLa cells. The media, time course, DFO, and small molecule treatments were the same as for the qRT-PCR assays. Cultured cells contained vehicle, HBS 1, or HBS 2 at a concentration of 50 μM. RNA was isolated as previously described. Sample preparation and microarray analysis was performed at the Genome Technology Center, New York University School of Medicine. Labeled mRNA was hybridized to Affymetrix Genechip Human Gene 1.0 ST microarrays. Four data sets were collected: normoxic cells with vehicle, hypoxic cells with vehicle, hypoxic cells with HBS 1, and hypoxic cells with HBS 2. Gene expression profiles were analyzed using GeneSpring GX 12.5 software (Agilent). Probe level data have been converted to expression values using a robust multi-array average (RMA) preprocessing procedure on the core probe sets and baseline transformation to median of all samples. A low-level filter removed the lowest 20 th  percentile of all the intensity values and generated a profile plot of filtered entities. Significance analysis was performed by one-way ANOVA test with Benjamini-Hochberg correction and asymptotic P-value computation. Fold change analysis was applied to identify genes with expression ratios above 1.1-fold between treatments and control set (P&lt;0.05). Hierarchical agglomerative clustering was performed using Pearson&#39;s centered correlation coefficient and average-linkage as distance and linkage methods. The gene expression profiling data have been deposited in the Gene Expression Omnibus (GEO) database, www.ncbi.nlm.nih.gov/GEO (accession no. GSE48002). 
     In Vivo Efficacy Tests of HBS 1 in Mouse Xenograft Tumor Models 
     CrTac:NCr-Foxn1 nu  mice (Taconic, Inc.) were used to examine the in vivo efficacy of HBS 1. Mice were housed in an A.L.A.C.C. approved barrier facility under the direct supervision of a professional veterinarian. Mice (n=6) were inoculated with 786-O cells (2×10 6  cells) into the right flank and allowed to grow tumors for 21 days. The primary endpoint of efficacy (the rate of increase in tumor volume as compared to control) were evaluated when mice were treated with HBS 1 at 13 mg/kg dissolved in sterile PBS given parenterally on days 4, 7, 11, 25, and 28, a total of 5 injections. In parallel, a control group (n=6) received injections of PBS. Tumor sizes were measured on Days 2, 3, 4, 6, 8, 11, 13, 16, 20, 25, 28, and 33. To address the question of whether tumor growth is affected by treatment with HBS, a comparison of the tumor volumes of the control group and the group treated with HBS 1 was made. At a conclusion of the study, mice were injected intraperitoneally with the near-infrared dye IR-783 contrast agent and the tumors were imaged using Xenogen IVIS 200 small animal imager. Euthanasia was performed as recommended by the American Veterinary Panel (AVMA 202229-249, 1993). The organs and tumors were collected for future histopathology studies. 
     Example 2 
     Design and Synthesis of Stabilized α-Helices 
     HIF-1α forms a heterodimer with its β subunit, aryl hydrocarbon receptor nuclear translocator (ARNT), to recognize hypoxia response element (HRE) and up-regulate expression of hypoxia-inducible genes, which are important contributors to tumor progression. Pyrrole-imidazole polyamides, which are programmable DNA-binding small molecules, have been shown to regulate transcription of hypoxia-inducible genes by binding to the HRE. Initiation of HIF-mediated transcription also requires complex formation between the CH1 domain of the coactivator protein p300 (or the homologous CREB binding protein, CBP) and the C-TAD 786-826  of HIF-1α( FIG. 3A ). This transcription factor-coactivator interaction represents an alternative target for controlling hypoxia signaling. Structural studies provide a molecular basis for this interaction and identify two short α-helical domains, αA and αB, from HIF-1α as key determinants for its recognition by p300 ( FIG. 3C ). Both αA and αB subdomains of HIF-1αC-TAD contain residues that contribute significantly to the complex formation, as shown by experimental mutagenesis studies. In earlier work, the αA peptide sequence was stabilized using the hydrogen bond surrogate (HBS) approach, which utilizes a carbon-carbon bond in place of the intramolecular hydrogen bond in α-helices. HBS helices have been shown to disrupt intracellular protein-protein interactions with high affinity and specificity. The αA mimetic was shown to downregulate mRNA levels of VEGF and GLUT1, two genes under the control of HIF-1α, while the linear peptide mimic of αA remained inactive. Importantly, the compound did not display significant toxicity as compared to chetomin, a small molecule known to target the same interaction. As described herein, the ability of αB mimics to inhibit the target interaction and control gene expression in cell culture was explored and its efficacy was tested in murine tumor xenograft models. 
     A key premise of rational design is that, unlike high throughput screening efforts, a handful of molecules that fit certain criteria need to be designed de novo. In an ideal scenario, these predictions would lead to both a potent ligand for the target receptor and a compound serving as a negative control, featuring minor alterations and binding the same protein with reduced affinity. Such a result would confirm the fundamental design principles while allowing the specificity of designed compounds to be evaluated. Accordingly, two stabilized helices based on the wild-type sequence were conceived ( FIG. 6A ), along with the unconstrained control ( FIG. 6B ). 
     HBS 1 is a direct mimic of HIF-1α 817-824  with the exception of Leu819, which was changed to an alanine residue to streamline synthetic effort (coupling of an N-alkyl alanine to the next residue is more efficient than coupling N-alkyl leucine). Computational alanine scanning mutagenesis analysis suggests that Leu819 is not a significant contributor to binding energy as opposed to Leu818, Leu822, Asp823, and Gln824 (see Table 4, supra). 
     HBS 2 was designed to be a specificity control in which the critical Leu-822 residue is replaced with an alanine; based on computational data, HBS 2 would be expected to bind CH1 with an order of magnitude weaker binding affinity than HBS 1. 
     Peptide 3 is an unconstrained analog of HBS 1; allowing the effect of helix stabilization on the activity of the compounds to be evaluated. The HBS helices were synthesized, purified, and characterized by HPLC and circular dichroism spectroscopy, as described above. As shown in  FIG. 7 , The constrained peptides showed characteristic α-helical circular dichroism spectroscopy signatures in aqueous buffers as compared to the unconstrained derivative, which displays no discernible helicity, as expected for a very short peptide. 
     Example 3 
     Designed Ligands Target p300-CH1 in a Predictive Manner 
     The CH1 domain of p300/CBP is stabilized by three zinc ions. Prior NMR structural studies have shown that the purified protein can rapidly aggregate in a buffer with excess or deficiency in Zn 2+  (Patgiri et al., “A Hydrogen Bond Surrogate Approach for Stabilization of Short Peptide Sequences in Alpha-Helical Conformation,”  Acc. Chem. Res.  41(10):1289-300 (2008), which is hereby incorporated by reference in its entirety). Attempts to evaluate binding of compounds with this protein have repeatedly resulted in protein aggregation and precipitation, even at low micromolar protein concentrations. The difficulty in working with this protein is directly correlated with its expression protocol, and slight changes in the concentrations of Zn 2+  in the bacterial growth media, supplemented with ZnSO 4 , could lead to purified protein samples that bind with different binding affinities (K d ˜30 nM-2 μM) to HIF-1αC-TAD 786-826 . To overcome this variability,  15 N labeled protein was prepared and peak dispersion (and protein folding) was monitored by  1 H- 15 N HSQC NMR experiments ( FIGS. 8A-D ). This  15 N-labeled, properly folded protein with the optimal levels of zinc shows a diminished tendency to aggregate and was used for binding assays. 
     The affinity of peptides for the  15 N-labeled p300 CH1 domain was evaluated using tryptophan fluorescence spectroscopy. The intrinsic fluorescence intensity of Trp403 has been shown to be a sensitive probe for CH1 folding. Significantly, this tryptophan lies in the αB binding pocket of p300/CBP, providing a unique probe for interrogating direct binding of αB mimics ( FIG. 9 ). Using this fluorescence method, HBS 1 was calculated to bind to p300-CH1 with a dissociation constant, K d , of 690±25 nM ( FIG. 5A  and  FIG. 10 ). For comparison, HIF-1αC-TAD 786-826  binds p300-CH1 with a K d  of 38±0.14 nM under the same conditions. The binding affinity of HIF-1αC-TAD to CH1 in this assay is consistent with that obtained from a fluorescence polarization assay using fluorescein-labeled HIF-1αC-TAD ( FIG. 11  and  FIG. 12 ) and those using isothermal titration microcalorimetry. The designed specificity control, HBS 2, targets CH1 with a four-fold weaker binding affinity (K d =2820±140 nM), supporting the computational predictions. Peptide 3 is an unconstrained analog of HBS 1 and binds the CH1 domain with a K d  of 6060±320 nM. These result indicate that stabilization of the peptide conformation offers a 9-fold increase in binding affinity. 
     To further characterize the interaction of HBS 1 with the CH1 domain,  1 H- 15 N HSQC NMR titration experiments were performed with uniformly  15 N-labeled CH1. Addition of HBS 1 to 69 μM CH1 in CH1:HBS 1 ratios of 1:1, 1:3, 1:5, and 1:10 resulted in a concentration-dependent shift in the resonances of several CH1 residues ( FIG. 5B ,  FIG. 13 , and  FIG. 14 ). Specifically, addition of FIBS 1 leads to shifts in the resonances of residues corresponding to the cleft into which the αB helix of HIF binds. This cleft includes Trp403 and chemical shift perturbations observed for this residue support the results of the fluorescence titration experiments. The CH1 domain binds to numerous proteins and has been termed a scaffold for protein folding. Earlier NMR studies have suggested that Zn 2+ -bound CH1 has a relatively rigid structure, although evidence of plasticity in CH1 has also been discussed. The HSQC titration experiment with HBS 1 described herein supports the view that CH1 has a stable conformation that does not reorganize substantially, at least upon binding of small ligands. Titration of HBS 1 to zinc-bound CH1 led to a relatively large shift in the side chain indole NH of W403 as compared to the backbone amide proton of this residue, suggesting that side chain repacking governs binding of these partners. 
     Example 4 
     HBS 1 Disrupts the HIF-1α/p300-CH1 Complex In Vitro 
     A fluorescence polarization assay was used to evaluate the ability of HBS 1 to inhibit the binding of fluorescein-labeled HIF-1αC-TAD 786-826  domain to p300-CH1. Addition of HBS 1 to the preformed protein complex provided a concentration-dependent decrease in fluorescence polarization with an inhibitory constant, K i , of 3.5±1.2 μM ( FIG. 5C ). Titration of HBS 2 or peptide 3 did not lead to reproducible inhibition of the complex, as expected from their weaker affinity for the CH1 domain. 
     Example 5 
     HBS 1 Downregulates Hypoxia-Inducible Gene Expression and VEGF Protein Levels in Hypoxic Cells 
     Based on the confirmed ability of HBS 1 to bind purified p300-CH1 and disrupt CH1/HIF-1αC-TAD 786-826  complex formation, its potential to downregulate the hypoxia-inducible promoter activity was evaluated in a luciferase-based reporter gene system. A construct containing five tandem repeats of the HRE consensus sequence found in the VEGF promoter (TACGTGGG (SEQ ID NO: 22)) cloned upstream of the hCMV minimal promoter was used to drive expression of firefly luciferase. This construct was stably transfected into a triple-negative breast cancer (TNBC) cell, MDA-MB-231, that does not express estrogen or progesterone receptors or exhibit HER-2/Neu amplification. The cells were subsequently treated with the peptides. Hypoxia was mimicked by placing cells into a GasPak EZ pouch. Under these conditions, treatment with HBS 1 at a concentration of 50 μM reduced luciferase expression by 25% ( FIG. 15 ). At the same concentrations, specificity control HBS 2 and unconstrained peptide 3 were found to be less effective. Despite the moderate extent of inhibition of the promoter activity, these results are encouraging, because MDA-MB-231 cells are aggressive and under hypoxia conditions exhibit confluence-dependent resistance to some anticancer drugs. The luciferase reporter assays described herein suggest that treatment with HBS 1 results in a statistically significant down-regulation of HIF-1α-inducible transcription in this cell line. 
     To exclude the possibility that the observed down-regulation in the expression of hypoxia-inducible genes was due to a change in the levels of HIF-1α protein itself, a western blot analysis of HIF-1α was performed in hypoxic cells treated with HBS 1. HIF-1α protein was not detectable under normoxia but is strongly induced under hypoxia mimetic conditions. As expected, the levels of induced HIF-1α protein were unaffected by treatment with HBS 1 ( FIG. 16 ). 
     The ability of HBS 1 and HBS 2 to inhibit hypoxia-induced transcription of target genes (VEGFA, SLC2A1/GLUT-1, and LOX) was evaluated employing real-time quantitative RT-PCR (qRT-PCR) assays. The data from the qRT-PCR experiments are presented in  FIGS. 17A-D . HBS 1 reduced expression levels of VEGF by 50% at 10 μM and greater than 60% at 50 μM showing marked dose dependence. In contrast, HBS 2 reduced expression levels of this gene by only 10% at 50 μM and peptide 3 was completely ineffective even at 50 μM concentration ( FIG. 17A ). Next, it was determined whether this inhibition could be observed for other therapeutically relevant hypoxia-inducible genes. The expression of the SLC2A1 (GLUT1) gene, one of the markers of glycolysis in tumors, and LOX, the hypoxia-inducible gene that has been shown to promote metastasis, were examined. In HeLa cells under hypoxia conditions, HBS 1 showed dose-dependent inhibition of SLC2A1 by 50-60%, comparable to that of VEGF gene in the same cell line ( FIG. 17B ). Similarly, HBS 1 significantly downregulated levels of expression of the LOX gene in a dose-dependent manner (55% and 70%, respectively,  FIG. 17C ). HBS 2 showed no activity in these assays, while peptide 3 had a reduced activity of 25%. To rule out the possibility that the compounds are only efficacious under DFO mimicked hypoxia, the efficacies of the HBS peptides in downregulating VEGF gene expression were compared under two different hypoxia mimetic conditions: DFO and prolonged incubation in an anaerobic pouch. Under both conditions, HBS 1 showed dose-dependent inhibition of VEGF expression ( FIG. 17D ). Next, the effect of HBS 1 treatment on the levels of secreted VEGF protein was assessed. An ELISA assay shows that HBS 1 downregulates VEGF protein levels in HeLa cells in a dose-dependent manner ( FIG. 18 ). 
     HBS 1 is an efficient modulator of contacts between HIF-1α and p300/CBP. Known inhibitors of this interaction typically function allosterically, by inducing unfolding of p300/CBP through abstraction of zinc ions. This could lead to non-specific abstraction of metal ions from other biomolecules (Block et al., “Direct Inhibition of Hypoxia-Inducible Transcription Factor Complex With Designed Dimeric Epidithiodiketopiperazine,”  J. Am. Chem. Soc.  131(50):18078-88 (2009), which is hereby incorporated by reference in its entirety). It was predicted that the HIF-1α mimetics should manifest their function in a more specific manner, and should not be generally cytotoxic. Cell viability assays confirm this hypothesis. It was found that HBS 1 is essentially non-cytotoxic within the entire range of tested concentrations (1 to 100 μM) ( FIG. 19 ). Interestingly, HBS 2 shows higher level of cytotoxicity than HBS 1, suggesting that this compound may be interacting with a different set of biomolecular targets as seen from gene expression profiling data (vide infra). Thus, HBS 2 may not just be a straightforward lower affinity analog of HBS 1 as designed. 
     Example 6 
     Gene Expression Profiling 
     Proteins p300 and CBP are pleiotropic multi-domain coactivators that directly interact with multiple transcription factors. One potential limitation of the use of coactivator-targeting ligands to control gene expression is that the compounds could lead to inhibition of large numbers of genes that depend on the function of p300 or CBP. Affymetrix Human Gene ST 1.0 arrays containing oligonucleotide sequences representing over 28,000 transcripts were used to evaluate the genome-wide effects of HBS 1 and 2 under hypoxia conditions. Gene expression levels were normalized to DFO-treated cells. 
     In hypoxic cells, clustering identified over 5,000 genes that changed in expression levels under one of the specified treatments: DFO, DFO+HBS 1, or DFO+HBS 2 ( FIGS. 20A-C ). Treatment with HBS 1 affected the expression of 122 transcripts by at least 1.1-fold (P&lt;0.05), while at the same threshold, control HBS 2 affected expression of 155 transcripts ( FIG. 20A  and  FIG. 20C ) (see Table 5 below). Remarkably, only 33 transcripts were overlapping, indicating that the subtle difference in structure between these two compounds results in a significant difference in genome-wide effects. For comparison, DFO treatment alone affected the expression of 368 transcripts. Clustering analysis was performed to identify similarities in the expression profiles between the different treatments ( FIG. 20A ). The expression profile of cells treated with HBS 1 resembles the profile of cells treated with DFO under the conditions of the analysis and, as mentioned above, is different from the profile of cells treated with HBS 2 despite the structural similarity between the two compounds. As expected, the expression profile of the normoxic cells is significantly different from the other three profiles. Analysis of transcripts affected by both HBS 1 and HBS 2 shows that only 28 and 5 transcripts are commonly down- and up-regulated, respectively, by at least 1.1-fold (P&lt;0.05). It is not surprising that there is some overlap in genes affected by both compounds given the complexity of cellular signaling pathways involved in the hypoxic response. It was found that DFO induced the expression of 45 transcripts by at least 4-fold (P&lt;0.05) ( FIG. 20B ). Within this dataset, multiple genes that belong to the hypoxia-inducible pathway were identified. HBS 1 and, to some extent HBS 2, affected almost all genes in this set. 
     
       
         
           
               
             
               
                 TABLE 5 
               
             
            
               
                   
               
               
                 Genes Affected at Least 2-Fold 
               
            
           
           
               
               
               
               
            
               
                 HBS 1 
                 HBS 2 
                 Control 
                   
               
            
           
           
               
               
               
               
               
               
               
            
               
                 Fold Change a   
                 Regulation b   
                 Fold Change c   
                 Regulation d   
                 Fold Change e    
                 Regulation f   
                 Gene 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
            
               
                 −1.198858  
                 down 
                 1.0873405 
                 up 
                 −2.7937474 
                 down 
                 ACADSB 
               
               
                 −1.1193628 
                 down 
                 −1.0069169 
                 down 
                 −5.2134614 
                 down 
                 ADM g   
               
               
                 −1.0377777  
                 down 
                 1.0465231  
                 up 
                 −2.6769848 
                 down 
                 AK4 
               
               
                 1.0583212 
                 up 
                 1.0463357 
                 up 
                 −7.2367773 
                 down 
                 ALDOC 
               
               
                 −1.0139477  
                 down 
                 −1.0427985 
                 down 
                 −2.587384 
                 down 
                 ANG/RNASE4 
               
               
                 −1.2298646  
                 down 
                 1.1285037  
                 up 
                 −10.575636 
                 down 
                 ANGPTL4 h   
               
               
                 −1.1789749 
                 down 
                 −1.1638044 
                 down 
                 −4.183105 
                 down 
                 ANKRD37/UFSP2 
               
               
                 −1.0263045  
                 down 
                 1.0068687  
                 up 
                 −2.3972414 
                 down 
                 ANKZF1 
               
               
                 1.031184  
                 up 
                 1.2810616 
                 up 
                 −2.1560726 
                 down 
                 ARHGAP28 
               
               
                 −1.0132513  
                 down 
                 1.0610821  
                 up 
                 −2.1491668 
                 down 
                 ARID5A 
               
               
                 −1.129277  
                 down 
                 1.0992572 
                 up 
                 −2.0692933 
                 down 
                 ARNTL 
               
               
                 −1.1177615 
                 down 
                 1.0696565 
                 up 
                 −3.0109265 
                 down 
                 ARRDC3 
               
               
                 −1.0990012  
                 down 
                 1.1408451  
                 up 
                 2.5837471 
                 up 
                 ASF1A 
               
               
                 1.0872076  
                 up 
                 −1.0366824 
                 down 
                 2.6614487 
                 up 
                 ASPM 
               
               
                 1.0160675 
                 up 
                 1.1073034 
                 up 
                 2.3719292 
                 up 
                 AURKA 
               
               
                 −1.1789101 
                 down 
                 −1.4730334 
                 down 
                 −2.2839973 
                 down 
                 B4GALT4 
               
               
                 −1.0872284 
                 down 
                 1.0667108  
                 up 
                 −2.0636718 
                 down 
                 BAMBI 
               
               
                 −1.085233 
                 down 
                 1.0502583  
                 up 
                 −5.271643 
                 down 
                 BHLHE40 
               
               
                 1.0080966  
                 up 
                 1.1611822  
                 up 
                 −2.6880012 
                 down 
                 BHLHE41 
               
               
                 1.0014353  
                 up 
                 1.0378009  
                 up 
                 −4.253393 
                 down 
                 BNIP3 
               
               
                 1.0350374  
                 up 
                 1.0081419 
                 up 
                 −5.3825545 
                 down 
                 BNIP3 
               
               
                 −1.0603999 
                 down 
                 1.0625899  
                 up 
                 −2.9519002 
                 down 
                 BNIP3L 
               
               
                 1.0250388  
                 up 
                 1.2118976 
                 up 
                 2.8752487 
                 up 
                 C14orf126 
               
               
                 −1.0156919 
                 down 
                 −1.119514  
                 down 
                 −2.0949163 
                 down 
                 C17orf76 
               
               
                 −1.122034 
                 down 
                 1.2555315  
                 up 
                 −2.2554584 
                 down 
                 C18orf19 
               
               
                 −1.1636652  
                 down 
                 −1.0204964 
                 down 
                 −6.7090216 
                 down 
                 C1orf161 
               
               
                 1.0112627  
                 up 
                 1.055041  
                 up 
                 2.4008303 
                 up 
                 C1orf163 
               
               
                 1.0871853  
                 up 
                 1.0450536 
                 up 
                 −2.477235 
                 down 
                 C1QL1 
               
               
                 −1.0888706 
                 down 
                 1.094631 
                 up 
                 −2.9811425 
                 down 
                 C3orf58 
               
               
                 1.0302335 
                 up 
                 −1.0332097 
                 down 
                 −3.2238207 
                 down 
                 C4orf3 
               
               
                 −1.0864575 
                 down 
                 −1.0435097 
                 down 
                 −2.4261425 
                 down 
                 C7orf60 
               
               
                 −1.16587 
                 down 
                 −1.019874 
                 down 
                 −5.8869715 
                 down 
                 C7orf68 
               
               
                 −1.0614659 
                 down 
                 1.2146437 
                 up 
                 −4.0432177 
                 down 
                 C8orf22 
               
               
                 −1.1226574 
                 down 
                 −1.0902045 
                 down 
                 −2.3521466 
                 down 
                 CA12 g   
               
               
                 −1.108866 
                 down 
                 1.2376684 
                 up 
                 −2.48113 
                 down 
                 CA5B 
               
               
                 −1.0285702 
                 down 
                 1.0281031 
                 up 
                 −13.296545 
                 down 
                 CA9 g   
               
               
                 −1.0158687 
                 down 
                 1.0848932 
                 up 
                 −2.0076687 
                 down 
                 CASZ1 
               
               
                 −1.0112811 
                 down 
                 1.0325615 
                 up 
                 −2.894002 
                 down 
                 CASZ1 
               
               
                 −1.04192 
                 down 
                 −1.0768336 
                 down 
                 −2.0998538 
                 down 
                 CCDC80 
               
               
                 1.0444043 
                 up 
                 −1.1706614 
                 down 
                 3.457119 
                 up 
                 CCNB1 
               
               
                 −1.0530787 
                 down 
                 1.0920707 
                 up 
                 −2.177964 
                 down 
                 CCNG2 
               
               
                 1.0208882 
                 up 
                 1.2310097 
                 up 
                 2.8682868 
                 up 
                 CDC20 
               
               
                 1.0020553 
                 up 
                 −1.0429283 
                 down 
                 −2.8950524 
                 down 
                 CDCP1 
               
               
                 1.0366052 
                 up 
                 −1.0903391 
                 down 
                 −2.0103207 
                 down 
                 CDK18 
               
               
                 −1.0981873 
                 down 
                 1.118337 
                 up 
                 −2.5513883 
                 down 
                 CDKN1A g   
               
               
                 1.0392698 
                 up 
                 −1.0248924 
                 down 
                 3.2755635 
                 up 
                 CDKN3 
               
               
                 −1.0188439 
                 down 
                 −1.0173886 
                 down 
                 2.3782046 
                 up 
                 CENPA 
               
               
                 −1.0183533 
                 down 
                 −1.0308503 
                 down 
                 4.255259 
                 up 
                 CENPE 
               
               
                 −1.00388 
                 down 
                 1.118164 
                 up 
                 2.0237246 
                 up 
                 CHAC2 
               
               
                 −1.0851383 
                 down 
                 1.1683263 
                 up 
                 −2.276149 
                 down 
                 CNOT8 
               
               
                 −1.0972031 
                 down 
                 1.0588787 
                 up 
                 −2.2344368 
                 down 
                 CPOX 
               
               
                 1.1451077 
                 up 
                 1.2831794 
                 up 
                 −2.1453977 
                 down 
                 CXCL16 
               
               
                 −1.1843526 
                 down 
                 1.1076756 
                 up 
                 −2.5658453 
                 down 
                 CXCR4 
               
               
                 −1.0300819 
                 down 
                 1.2587326 
                 up 
                 −2.9216492 
                 down 
                 DAPK1 
               
               
                 1.0221276 
                 up 
                 1.0206687 
                 up 
                 2.4073172 
                 up 
                 DDX10 
               
               
                 1.0624138 
                 up 
                 −1.0969201 
                 down 
                 2.4726677 
                 up 
                 DEPDC1 
               
               
                 1.1574726 
                 up 
                 1.0593747 
                 up 
                 2.51015  
                 up 
                 DIS3L 
               
               
                 −1.0776646 
                 down 
                 −1.1640482 
                 down 
                 −2.1677356 
                 down 
                 DKFZp451A211 
               
               
                 −1.0658602 
                 down 
                 1.0331173 
                 up 
                 2.4103513 
                 up 
                 DLGAP5 
               
               
                 −1.1005502 
                 down 
                 −1.1672455 
                 down 
                 −2.8135295 
                 down 
                 DUSP5 
               
               
                 −1.3719523 
                 down 
                 −1.1782583 
                 down 
                 −2.2521324 
                 down 
                 DUSP5P 
               
               
                 1.0034794  
                 up 
                 −1.0582042 
                 down 
                 −2.2900689 
                 down 
                 DUSP9 
               
               
                 −1.0524148 
                 down 
                 1.2744057 
                 up 
                 2.864903 
                 up 
                 E2F5 
               
               
                 −1.0750257 
                 down 
                 −1.0517342 
                 down 
                 −2.33422 
                 down 
                 EDN2 g   
               
               
                 −1.0114882 
                 down 
                 1.0963054  
                 up 
                 −3.0769978 
                 down 
                 EFNA3 h   
               
               
                 −1.0063022 
                 down 
                 1.0588189  
                 up 
                 −3.1732266 
                 down 
                 EGLN1 g   
               
               
                 −1.0551443 
                 down 
                 1.247042  
                 up 
                 −5.1503882 
                 down 
                 EGLN3 g   
               
               
                 1.0174965  
                 up 
                 1.1876371  
                 up 
                 2.072199 
                 up 
                 ELOVL6 
               
               
                 −1.0733106 
                 down 
                 −1.06308  
                 down 
                 −10.603759 
                 down 
                 ENO2 g   
               
               
                 −1.0835003 
                 down 
                 1.0701011 
                 up 
                 −2.9529157 
                 down 
                 ERO1L 
               
               
                 −1.1790224 
                 down 
                 1.2047563  
                 up 
                 −3.7419317 
                 down 
                 ERRFI1 
               
               
                 −1.1053089 
                 down 
                 −1.0812296 
                 down 
                 −3.2845836 
                 down 
                 FAM115C 
               
               
                 −1.1265318 
                 down 
                 −1.0945897 
                 down 
                 −3.6846316 
                 down 
                 FAM115C/LOC154761 
               
               
                 −1.0174642 
                 down 
                 1.0516164  
                 up 
                 2.899864 
                 up 
                 FAM133A 
               
               
                 −1.1241008 
                 down 
                 −1.0209429 
                 down 
                 −2.5158167 
                 down 
                 FAM 13A 
               
               
                 −1.0018321 
                 down 
                 −1.0929846 
                 down 
                 −3.9271286 
                 down 
                 FAM162A 
               
               
                 1.0610536  
                 up 
                 −1.0276216 
                 down 
                 3.337046 
                 up 
                 FAM72D/FAM72A/FAM72B/FAM72C 
               
               
                 1.0634061  
                 up 
                 −1.0241611 
                 down 
                 3.3964236 
                 up 
                 FAM72D/FAM72A/FAM72B/FAM72C 
               
               
                 1.0337092  
                 up 
                 −1.030498  
                 down 
                 3.442782 
                 up 
                 FAM72D/FAM72A/FAM72B/FAM72C 
               
               
                 1.0572628  
                 up 
                 −1.0239878 
                 down 
                 3.331725 
                 up 
                 FAM72D/FAM72A/FAM72B/FAM72C 
               
               
                 1.0138565  
                 up 
                 −1.1081187 
                 down 
                 2.165065 
                 up 
                 FAM83D 
               
               
                 1.043707  
                 up 
                 −1.0308311 
                 down 
                 2.8210485 
                 up 
                 FAM86B1/ALG1/LOC645332/LOC653113 
               
               
                 1.068682  
                 up 
                 −1.0393488 
                 down 
                 2.2467046 
                 up 
                 FAM86B1/FAM86B2 
               
               
                 1.0729985  
                 up 
                 1.0761985  
                 up 
                 2.617571 
                 up 
                 FAM86B1/FAM86C 
               
               
                 1.0354363  
                 up 
                 −1.0027288 
                 down 
                 2.0040247 
                 up 
                 FAM86C 
               
               
                 −1.0094354 
                 down 
                 1.3029685  
                 up 
                 2.168605 
                 up 
                 FARSB 
               
               
                 1.140963  
                 up 
                 −1.1433238 
                 down 
                 −2.021754 
                 down 
                 FBXO32 
               
               
                 −1.0524883 
                 down 
                 1.0493332  
                 up 
                 −2.1420243 
                 down 
                 FBXO42 
               
               
                 1.2110548  
                 up 
                 1.0567071  
                 up 
                 2.0648973 
                 up 
                 FERMT1 
               
               
                 −1.0951974 
                 down 
                 −1.3137784 
                 down 
                 −2.025113 
                 down 
                 FN1 
               
               
                 −1.2603712 
                 down 
                 −1.1467572 
                 down 
                 −2.9039383 
                 down 
                 FOS 
               
               
                 1.0239884  
                 up 
                 −1.0724043 
                 down 
                 −2.2796876 
                 down 
                 FOXD1 
               
               
                 −1.0264313 
                 down 
                 1.0304923 
                 up 
                 −3.194702 
                 down 
                 FUT11/FLJ44715 
               
               
                 −1.038652 
                 down 
                 −1.0402472 
                 down 
                 −2.1154828 
                 down 
                 FXYD3 
               
               
                 −1.0902228 
                 down 
                 −1.1942844 
                 down 
                 −2.161142 
                 down 
                 FYN 
               
               
                 −1.0004762 
                 down 
                 1.0612249 
                 up 
                 2.1665447 
                 up 
                 G2E3 
               
               
                 −1.0668463 
                 down 
                 1.0567585 
                 up 
                 −2.9950464 
                 down 
                 GBE1 
               
               
                 −1.2743438 
                 down 
                 1.0132078 
                 up 
                 −2.805562 
                 down 
                 GDF15 
               
               
                 1.0969177 
                 up 
                 1.0458834 
                 up 
                 2.522929  
                 up 
                 GEMIN5 
               
               
                 −1.326227 
                 down 
                 1.1455405 
                 up 
                 −2.8021276 
                 down 
                 GFPT2 
               
               
                 −1.2790403 
                 down 
                 −1.3487692 
                 down 
                 −3.023291 
                 down 
                 GOLGA8B/GOLGA8A 
               
               
                 −1.265511 
                 down 
                 −1.329899 
                 down 
                 −2.905124 
                 down 
                 GOLGA8B/GOLGA8A 
               
               
                 1.0313923 
                 up 
                 −1.1114029 
                 down 
                 2.2596123 
                 up 
                 GPATCH4 
               
               
                 −1.1066624 
                 down 
                 −1.032009 
                 down 
                 −5.079305 
                 down 
                 GPR146 
               
               
                 −1.1756448 
                 down 
                 1.1828246 
                 up 
                 −3.0940225 
                 down 
                 GPR155 
               
               
                 1.0572137 
                 up 
                 −1.0137892 
                 down 
                 −2.6079721 
                 down 
                 GPR160 
               
               
                 −1.0540816 
                 down 
                 1.0293025 
                 up 
                 −2.0090497 
                 down 
                 GPRC5A 
               
               
                 −1.0433288 
                 down 
                 1.0330802 
                 up 
                 −2.6747115 
                 down 
                 GPT2 
               
               
                 −1.089778 
                 down 
                 1.1071146 
                 up 
                 −2.0776129 
                 down 
                 GTF2IRD2/GTF2IRD2B 
               
               
                 −1.0697725 
                 down 
                 1.1319958 
                 up 
                 −2.1862717 
                 down 
                 GTF2IRD2B 
               
               
                 −1.0347298 
                 down 
                 −1.0523677 
                 down 
                 −2.2005339 
                 down 
                 GYS1 
               
               
                 −1.033671 
                 down 
                 1.2477574 
                 up 
                 3.2375476 
                 up 
                 H1F0 
               
               
                 −1.0744232 
                 down 
                 −1.2446554 
                 down 
                 −2.049202 
                 down 
                 HAS2 
               
               
                 −1.1388015 
                 down 
                 1.1164491 
                 up 
                 −3.110763 
                 down 
                 HERC3 
               
               
                 −1.0328522 
                 down 
                 −1.0706353 
                 down 
                 −2.247471 
                 down 
                 HEY1 
               
               
                 −1.0139298 
                 down 
                 −1.1250477 
                 down 
                 2.4303255 
                 up 
                 HIST1H1C 
               
               
                 −1.0382714 
                 down 
                 1.2453547 
                 up 
                 2.1910377 
                 up 
                 HIST1H1E 
               
               
                 1.1814293 
                 up 
                 −1.0565162 
                 down 
                 4.548209  
                 up 
                 HIST1H2AB 
               
               
                 1.028249 
                 up 
                 1.0202644 
                 up 
                 2.5113926 
                 up 
                 HIST1H2AC 
               
               
                 1.0760688 
                 up 
                 1.0016093 
                 up 
                 2.7375612 
                 up 
                 HIST1H2AE 
               
               
                 1.0772592 
                 up 
                 1.0379401 
                 up 
                 2.6594944 
                 up 
                 HIST1H2AH 
               
               
                 1.088042 
                 up 
                 −1.0238472 
                 down 
                 3.1786556 
                 up 
                 HIST1H2AI 
               
               
                 1.0760545 
                 up 
                 1.0216632 
                 up 
                 3.3433473 
                 up 
                 HIST1H2AI/HIST1H3H 
               
               
                 1.0729878 
                 up 
                 1.01679  
                 up 
                 3.328223  
                 up 
                 HIST1H2AK/HIST1H2BN 
               
               
                 1.0669847 
                 up 
                 1.097534 
                 up 
                 2.094609  
                 up 
                 HIST1H2AL 
               
               
                 1.1164097 
                 up 
                 1.0291708 
                 up 
                 2.655007  
                 up 
                 HIST1H2BC 
               
               
                 1.0628002 
                 up 
                 1.1290944 
                 up 
                 3.553227  
                 up 
                 HIST1H2BF 
               
               
                 1.0641918 
                 up 
                 −1.038236 
                 down 
                 4.369798  
                 up 
                 HIST1H2BG 
               
               
                 1.1094822 
                 up 
                 1.0056278 
                 up 
                 3.8479862  
                 up 
                 HIST1H2BH 
               
               
                 1.0249968 
                 up 
                 −1.0275244 
                 down 
                 3.34124  
                 up 
                 HIST1H2BI 
               
               
                 −1.011945 
                 down 
                 −1.0242423 
                 down 
                 2.3438275  
                 up 
                 HIST1H2BJ 
               
               
                 −1.0310844 
                 down 
                 1.5378659 
                 up 
                 2.0198417  
                 up 
                 HIST1H2BK 
               
               
                 1.0454845 
                 up 
                 1.0881157 
                 up 
                 2.6407917  
                 up 
                 HIST1H2BK/HIST1H2BE/H2BFS 
               
               
                 1.1658144 
                 up 
                 1.0298574 
                 up 
                 12.502561  
                 up 
                 HIST1H2BM 
               
               
                 1.067194 
                 up 
                 1.0149908 
                 up 
                 2.9552643  
                 up 
                 HIST1H3A 
               
               
                 1.015362 
                 up 
                 1.0197564 
                 up 
                 2.8443613  
                 up 
                 HIST1H3D/HIST1H2AD 
               
               
                 1.1092883 
                 up 
                 −1.688728 
                 down 
                 3.1881328  
                 up 
                 HIST1H3F 
               
               
                 1.0364317 
                 up 
                 1.0101742 
                 up 
                 2.6978357  
                 up 
                 HIST1H3H 
               
               
                 1.1638831 
                 up 
                 −1.3748453 
                 down 
                 3.6814818  
                 up 
                 HIST1H4B 
               
               
                 1.0328214 
                 up 
                 −1.316773 
                 down 
                 2.1798692  
                 up 
                 HIST1H4H 
               
               
                 1.0930722 
                 up 
                 −1.166608 
                 down 
                 3.6174786  
                 up 
                 HIST1H4J/HIST1H4K 
               
               
                 1.1102779 
                 up 
                 −1.1824476 
                 down 
                 3.8873343  
                 up 
                 HIST1H4K/HIST1H4J 
               
               
                 1.0088866 
                 up 
                 1.0189656 
                 up 
                 2.1680818  
                 up 
                 HIST2H2AA3/HIST2H2AA4/HIST2H2AC 
               
               
                 1.0085102 
                 up 
                 1.0195583 
                 up 
                 2.1686635  
                 up 
                 HIST2H2AA3/HIST2H2AA4/HIST2H2AC 
               
               
                 1.2118632 
                 up 
                 1.1212372 
                 up 
                 2.66082  
                 up 
                 HIST2H2AB 
               
               
                 1.0203393 
                 up 
                 −1.1051214 
                 down 
                 2.6113982  
                 up 
                 HIST2H2AC/BOLA1 
               
               
                 1.0405347 
                 up 
                 1.0846759 
                 up 
                 2.0019317  
                 up 
                 HIST2H2BA/HIST2H2BF 
               
               
                 1.032434 
                 up 
                 1.0164887 
                 up 
                 2.8465867  
                 up 
                 HIST2H2BE 
               
               
                 1.1210366 
                 up 
                 −1.0613894 
                 down 
                 2.0390704  
                 up 
                 HIST2H3D/HIST2H3A/HIST2H3C 
               
               
                 −1.194571 
                 down 
                 1.121211 
                 up 
                 2.1261342  
                 up 
                 HIST2H4A/HIST2H4B 
               
               
                 −1.1939466 
                 down 
                 1.1216862 
                 up 
                 2.1261613  
                 up 
                 HIST2H4A/HIST2H4B 
               
               
                 1.0092357 
                 up 
                 1.0444485 
                 up 
                 2.094921  
                 up 
                 HIST3H2A 
               
               
                 −1.0752294 
                 down 
                 1.0338196 
                 up 
                 −3.9728498 
                 down 
                 HIVEP2 
               
               
                 −1.1303259 
                 down 
                 1.1321235 
                 up 
                 −2.133175  
                 down 
                 HK1 g   
               
               
                 −1.0533404 
                 down 
                 −1.0264349 
                 down 
                 −5.7125254 
                 down 
                 HK2 g   
               
               
                 1.1010088 
                 up 
                 1.1335866 
                 up 
                 4.111633  
                 up 
                 HMMR 
               
               
                 −1.0138937 
                 down 
                 1.2460188 
                 up 
                 2.145269 
                 up 
                 HORMAD1 
               
               
                 −1.0750805 
                 down 
                 −1.0380528 
                 down 
                 −2.1026213 
                 down 
                 HOXD10 
               
               
                 1.1196996  
                 up 
                 1.1180418 
                 up 
                 2.7761664 
                 up 
                 HPDL 
               
               
                 −1.1325891 
                 down 
                 1.0055424 
                 up 
                 −2.4589784 
                 down 
                 HRH1 
               
               
                 −1.1192311 
                 down 
                 1.0154862 
                 up 
                 2.0284126 
                 up 
                 HSPA1A/HSPA1B 
               
               
                 −1.1208296 
                 down 
                 1.0085618 
                 up 
                 2.0253496 
                 up 
                 HSPA1A/HSPA1B 
               
               
                 −1.1177293 
                 down 
                 −1.0437095 
                 down 
                 2.0822313 
                 up 
                 HSPA1B/HSPA1A 
               
               
                 −1.1122378 
                 down 
                 −1.0498594 
                 down 
                 2.0941586 
                 up 
                 HSPA1B/HSPA1A 
               
               
                 −1.112368  
                 down 
                 −1.0498853 
                 down 
                 2.0940685 
                 up 
                 HSPA1B/HSPA1A 
               
               
                 1.2337483  
                 up 
                 −1.5396951 
                 down 
                 2.4555218 
                 up 
                 ID3 
               
               
                 1.1887107  
                 up 
                 −1.1141586 
                 down 
                 −2.5604243 
                 down 
                 IDH2 
               
               
                 −1.3824807 
                 down 
                 1.1527516 
                 up 
                 −4.497776 
                 down 
                 IER3 
               
               
                 −1.3749976 
                 down 
                 1.1767937 
                 up 
                 −4.707593 
                 down 
                 IER3 
               
               
                 −1.3823622 
                 down 
                 1.153014  
                 up 
                 −4.500477 
                 down 
                 IER3 
               
               
                 −1.1800597 
                 down 
                 1.0211127 
                 up 
                 −4.437638 
                 down 
                 IGFBP3 
               
               
                 −1.121893  
                 down 
                 −1.1431843 
                 down 
                 −2.0187001 
                 down 
                 IGSF3 
               
               
                 −1.0634735 
                 down 
                 −1.4005892 
                 down 
                 −2.1043446 
                 down 
                 IL1RAP 
               
               
                 −1.3237284 
                 down 
                 1.0446229 
                 up 
                 −5.254703 
                 down 
                 IL2RG 
               
               
                 −1.053483  
                 down 
                 −1.0516862 
                 down 
                 −2.0464828 
                 down 
                 ING2 
               
               
                 −1.0689135 
                 down 
                 1.3293185 
                 up 
                 −2.1875443 
                 down 
                 INSIG1 
               
               
                 −1.2234808 
                 down 
                 1.0493531 
                 up 
                 −7.2295227 
                 down 
                 INSIG2 
               
               
                 −1.0548623 
                 down 
                 1.0914948 
                 up 
                 −2.2711992 
                 down 
                 IPMK 
               
               
                 −1.104967  
                 down 
                 −1.1261146 
                 down 
                 −5.4967833 
                 down 
                 ITGA5 
               
               
                 −1.2723838 
                 down 
                 −1.4516369 
                 down 
                 −4.7319503 
                 down 
                 JUN 
               
               
                 −1.0761135 
                 down 
                 −1.0448471 
                 down 
                 −2.08533 
                 down 
                 KAT2B 
               
               
                 −1.069219  
                 down 
                 −1.1738038 
                 down 
                 −3.964814 
                 down 
                 KCTD11 
               
               
                 −1.0983505 
                 down 
                 −1.0338085 
                 down 
                 −4.5585265 
                 down 
                 KDM3A 
               
               
                 1.0428305  
                 up 
                 1.0739981 
                 up 
                 2.0221412 
                 up 
                 KIAA0586 
               
               
                 −1.0484446 
                 down 
                 −1.000957 
                 down 
                 −5.1322355 
                 down 
                 KIAA1244 
               
               
                 −1.0863793 
                 down 
                 1.0911593 
                 up 
                 −2.0486183 
                 down 
                 KIAA1432 
               
               
                 −1.0647811 
                 down 
                 1.1031417 
                 up 
                 −2.3516953 
                 down 
                 KIAA1715 
               
               
                 −1.1583545 
                 down 
                 −1.0508852 
                 down 
                 2.1151373 
                 up 
                 KIF14 
               
               
                 −1.00198  
                 down 
                 −1.0037445 
                 down 
                 3.4379961  
                 up 
                 KIF20A/CDC23 
               
               
                 1.1104406  
                 up 
                 −1.6264613 
                 down 
                 −2.1513863  
                 down 
                 KRT17 
               
               
                 1.1725253  
                 up 
                 −1.8421245 
                 down 
                 −2.5044134  
                 down 
                 KRT17 
               
               
                 −1.0665327 
                 down 
                 1.024981 
                 up 
                 −7.6152425  
                 down 
                 LOX g   
               
               
                 −1.0239133 
                 down 
                 −1.0096284 
                 down 
                 −3.1381226  
                 down 
                 LOXL2 
               
               
                 −1.0881166 
                 down 
                 −1.1607536 
                 down 
                 −2.4658139  
                 down 
                 LRP1 
               
               
                 −1.0412775 
                 down 
                 1.0400462 
                 up 
                 2.0927668  
                 up 
                 LTV1 
               
               
                 −1.1852337 
                 down 
                 −1.4142182 
                 down 
                 −2.1554024  
                 down 
                 MAFB 
               
               
                 −1.0526593 
                 down 
                 −1.1299944 
                 down 
                 −2.1507175  
                 down 
                 MAFK/TMEM184A 
               
               
                 1.0472041  
                 up 
                 −1.0342416 
                 down 
                 2.0437317  
                 up 
                 MAK16/C8orf41 
               
               
                 −1.0581415 
                 down 
                 1.0291281 
                 up 
                 −2.0293536  
                 down 
                 MAP2K1/SNAPC5 
               
               
                 −1.0998803 
                 down 
                 −1.0539637 
                 down 
                 −2.8863204  
                 down 
                 MAP3K15/PDHA1 
               
               
                 −1.1232924 
                 down 
                 1.6498638 
                 up 
                 2.2023304  
                 up 
                 METTL7A 
               
               
                 1.0905137  
                 up 
                 1.0289348 
                 up 
                 2.175937  
                 up 
                 MLKL 
               
               
                 −1.0716023 
                 down 
                 1.0461466 
                 up 
                 −2.0215554  
                 down 
                 MOBKL2A 
               
               
                 1.1000898  
                 up 
                 −1.0295926 
                 down 
                 2.5916712  
                 up 
                 MSTO1/MSTO2P 
               
               
                 1.1853988  
                 up 
                 −1.0830567 
                 down 
                 2.580263  
                 up 
                 MSTO2P/MSTO1 
               
               
                 −1.0930141 
                 down 
                 1.0225625 
                 up 
                 −3.293971  
                 down 
                 MUC1 
               
               
                 −1.014464  
                 down 
                 −1.0215149 
                 down 
                 −2.346065  
                 down 
                 MXI1 
               
               
                 −1.072508  
                 down 
                 1.1463394 
                 up 
                 −2.0467393  
                 down 
                 NAMPT 
               
               
                 −1.0733447 
                 down 
                 1.1515353 
                 up 
                 −2.0046158  
                 down 
                 NAMPT 
               
               
                 −1.0171611 
                 down 
                 1.1263885 
                 up 
                 2.024874  
                 up 
                 NARS2 
               
               
                 −1.0521922 
                 down 
                 −1.0211507 
                 down 
                 −2.179991  
                 down 
                 NAV1 
               
               
                 −1.0180564 
                 down 
                 1.0198303 
                 up 
                 −3.32679  
                 down 
                 NDRG1 g   
               
               
                 1.0553051  
                 up 
                 1.1875671 
                 up 
                 2.8213596  
                 up 
                 NDUFAF4 
               
               
                 1.0536773  
                 up 
                 −1.2928615 
                 down 
                 −2.193419  
                 down 
                 NEBL 
               
               
                 −1.0623983 
                 down 
                 −1.1545544 
                 down 
                 −3.262253  
                 down 
                 NFIL3 
               
               
                 1.0572549  
                 up 
                 1.0486796 
                 up 
                 2.1284277  
                 up 
                 NLN 
               
               
                 −1.3564715 
                 down 
                 1.412258 
                 up 
                 −2.0202577  
                 down 
                 NOG 
               
               
                 1.0569912  
                 up 
                 −1.0584995 
                 down 
                 2.6115415  
                 up 
                 NOL6 
               
               
                 1.0345374  
                 up 
                 −1.1083401 
                 down 
                 2.9392853  
                 up 
                 NOP16 
               
               
                 −1.0246124 
                 down 
                 −1.0321362 
                 down 
                 2.013658  
                 up 
                 NOP2 
               
               
                 −1.142908  
                 down 
                 −1.1094075 
                 down 
                 −2.1712103 
                 down 
                 NOTCH3 
               
               
                 −1.0493118 
                 down 
                 1.0916766 
                 up 
                 −2.094681 
                 down 
                 NRG4 
               
               
                 1.0453973  
                 up 
                 1.0413948 
                 up 
                 −2.9922984 
                 down 
                 ORAI3 
               
               
                 −1.2377601 
                 down 
                 −1.0565416 
                 down 
                 −3.1627083 
                 down 
                 OSMR 
               
               
                 −1.3154866 
                 down 
                 −1.2208521 
                 down 
                 −2.8162463 
                 down 
                 OTUD1 
               
               
                 −1.0067146 
                 down 
                 1.1961997 
                 up 
                 −4.525767 
                 down 
                 P4HA1 
               
               
                 −1.0518332 
                 down 
                 −1.0594456 
                 down 
                 −4.467532 
                 down 
                 P4HA2 
               
               
                 −1.0599507 
                 down 
                 −1.1152831 
                 down 
                 −2.7483146 
                 down 
                 PAG1 
               
               
                 −1.0068985 
                 down 
                 −1.0078048 
                 down 
                 −2.005217 
                 down 
                 PAIP2B 
               
               
                 −1.0382358 
                 down 
                 1.0521878 
                 up 
                 −4.557052 
                 down 
                 PDK1 
               
               
                 1.0191542  
                 up 
                 1.1393752 
                 up 
                 −3.8439698 
                 down 
                 PDK3 
               
               
                 −1.085743  
                 down 
                 1.1143924 
                 up 
                 −2.1830468 
                 down 
                 PER1 
               
               
                 −1.0596828 
                 down 
                 −1.0105202 
                 down 
                 −2.0410588 
                 down 
                 PER2 
               
               
                 −1.072292  
                 down 
                 −1.0640502 
                 down 
                 −9.719393 
                 down 
                 PFKF84 g   
               
               
                 −1.0348089 
                 down 
                 1.0235314 
                 up 
                 −3.3854454 
                 down 
                 PFKP 
               
               
                 −1.1552294 
                 down 
                 1.008007 
                 up 
                 −2.0849102 
                 down 
                 PGM2L1 
               
               
                 −1.0775337 
                 down 
                 1.1154193 
                 up 
                 −2.0587978 
                 down 
                 PIAS2 
               
               
                 −1.0306145 
                 down 
                 1.111947 
                 up 
                 2.663589  
                 up 
                 PLA2G4A 
               
               
                 −1.1131518 
                 down 
                 −1.1262151 
                 down 
                 −3.160247 
                 down 
                 PLAGL1/HYMAI 
               
               
                 −1.1653019 
                 down 
                 1.0859076 
                 up 
                 −2.9282918 
                 down 
                 PLIN2 
               
               
                 −1.0407479 
                 down 
                 1.018729 
                 up 
                 3.1841922 
                 up 
                 PLK1 
               
               
                 −1.0310947 
                 down 
                 −1.0200943 
                 down 
                 −2.051884 
                 down 
                 PLOD1 
               
               
                 −1.0564666 
                 down 
                 1.0334756 
                 up 
                 −2.6392682 
                 down 
                 PLOD2 
               
               
                 −1.0536163 
                 down 
                 −1.0217751 
                 down 
                 −2.9487426 
                 down 
                 PMEPA1 
               
               
                 −1.0364561 
                 down 
                 1.1446192 
                 up 
                 2.142106  
                 up 
                 PNO1 
               
               
                 1.0623838  
                 up 
                 1.1337379 
                 up 
                 2.3235378 
                 up 
                 POLR18 
               
               
                 −1.1132654 
                 down 
                 −1.2193453 
                 down 
                 −5.72456  
                 down 
                 PPFIA4/LOC100507405 
               
               
                 −1.0076138 
                 down 
                 −1.0337875 
                 down 
                 −2.3916671 
                 down 
                 PPL 
               
               
                 −1.0528351 
                 down 
                 −1.0763819 
                 down 
                 −2.0917118 
                 down 
                 PPP1R3B 
               
               
                 1.0514251  
                 up 
                 −1.0709876 
                 down 
                 −2.185088 
                 down 
                 PPP1R3C 
               
               
                 −1.0886943 
                 down 
                 −1.0989375 
                 down 
                 −4.635631 
                 down 
                 PPP2R5B 
               
               
                 1.0562048  
                 up 
                 1.0604632 
                 up 
                 2.006964  
                 up 
                 PPRC1 
               
               
                 −1.1171283 
                 down 
                 −1.0515006 
                 down 
                 −2.7193942 
                 down 
                 PRELID2 
               
               
                 1.0199716 
                 up 
                 −1.006938 
                 down 
                 2.2714365 
                 up 
                 PRMT3 
               
               
                 −1.493969 
                 down 
                 1.176382 
                 up 
                 −3.8572378 
                 down 
                 PTGS2 h   
               
               
                 1.0979699 
                 up 
                 −1.2585038 
                 down 
                 2.1313524 
                 up 
                 PTTG1 
               
               
                 −1.084285 
                 down 
                 −1.1066813 
                 down 
                 −2.243677 
                 down 
                 PYGL 
               
               
                 1.0216292 
                 up 
                 1.0164917 
                 up 
                 −2.9913483 
                 down 
                 QSOX1/FLJ23867 
               
               
                 −1.0165472 
                 down 
                 1.0808368 
                 up 
                 −2.4004233 
                 down 
                 RAB20 
               
               
                 −1.0168173 
                 down 
                 −1.0137872 
                 down 
                 −2.0478325 
                 down 
                 RAB40C 
               
               
                 −1.091034 
                 down 
                 1.0204805 
                 up 
                 −2.3124177 
                 down 
                 RAB8B 
               
               
                 1.0475962 
                 up 
                 1.1967145 
                 up 
                 −3.5479445 
                 down 
                 RASSF2 
               
               
                 −1.0217447 
                 down 
                 1.0673434 
                 up 
                 −3.8055146 
                 down 
                 RCOR2 
               
               
                 −1.0315185 
                 down 
                 −1.0285182 
                 down 
                 −2.5645835 
                 down 
                 RIOK3 
               
               
                 −1.057626 
                 down 
                 1.006583 
                 up 
                 −2.01166 
                 down 
                 RIT1 
               
               
                 −1.1474804 
                 down 
                 1.0842069 
                 up 
                 −2.3212476 
                 down 
                 RLF 
               
               
                 1.0111393 
                 up 
                 −1.0896454 
                 down 
                 −3.0329592 
                 down 
                 RNF122 
               
               
                 −1.0728997 
                 down 
                 1.109433 
                 up 
                 −2.6993163 
                 down 
                 RNF24 
               
               
                 1.0031627 
                 up 
                 −2.735376 
                 down 
                 −1.2172973 
                 down 
                 RNU4-2 
               
               
                 −1.1661395 
                 down 
                 1.0366671 
                 up 
                 −6.9026365 
                 down 
                 RORA 
               
               
                 −1.0086578 
                 down 
                 −1.1610154 
                 down 
                 −4.0498514 
                 down 
                 RRAGD 
               
               
                 1.080574 
                 up 
                 1.0721519 
                 up 
                 2.8641217 
                 up 
                 RRS1 
               
               
                 1.0885082 
                 up 
                 −1.0089406 
                 down 
                 2.097932 
                 up 
                 RUVBL1 
               
               
                 −1.1617795 
                 down 
                 −2.3124695 
                 down 
                 −1.2749236 
                 down 
                 SCARNA5 
               
               
                 −1.153035 
                 down 
                 −2.4092975 
                 down 
                 −1.2401854 
                 down 
                 SCARNA6 
               
               
                 1.1310145 
                 up 
                 1.0209829 
                 up 
                 2.0414371 
                 up 
                 SCFD2 
               
               
                 −1.0548553 
                 down 
                 1.0334789 
                 up 
                 −2.9133189 
                 down 
                 SEC14L4 
               
               
                 −1.0628065 
                 down 
                 −1.0827417 
                 down 
                 −2.5861993 
                 down 
                 SEC61G 
               
               
                 −1.112961 
                 down 
                 −1.0562894 
                 down 
                 −2.7914515 
                 down 
                 SERPINE1 g   
               
               
                 −1.163552 
                 down 
                 −1.2216003 
                 down 
                 −2.6976469 
                 down 
                 SERPINI1 
               
               
                 −1.0688736 
                 down 
                 1.0619785 
                 up 
                 −2.3279095 
                 down 
                 SERTAD2 
               
               
                 1.0343328 
                 up 
                 1.1705835 
                 up 
                 2.0703044 
                 up 
                 SLC27A2 
               
               
                 −1.1072197 
                 down 
                 1.1236045 
                 up 
                 −2.8005152 
                 down 
                 SLC2A1 g   
               
               
                 −1.0290065 
                 down 
                 1.053982 
                 up 
                 −4.183235 
                 down 
                 SLC2A3 
               
               
                 −1.248505 
                 down 
                 1.2203912 
                 up 
                 −2.266289 
                 down 
                 SLC6A6 
               
               
                 −1.0604588 
                 down 
                 1.0595843 
                 up 
                 −2.7195609 
                 down 
                 SLC6A8/SLC6A10P 
               
               
                 −1.0662978 
                 down 
                 1.0684845 
                 up 
                 −2.736111 
                 down 
                 SLC6A8/SLC6A10P 
               
               
                 −1.0853571 
                 down 
                 1.2627056 
                 up 
                 2.0000556 
                 up 
                 SLC7A11 
               
               
                 −1.2457515 
                 down 
                 −1.0702848 
                 down 
                 −5.947674 
                 down 
                 SLCO1B3/LST-3TM12 
               
               
                 −1.2625779 
                 down 
                 1.252622 
                 up 
                 −2.0586894 
                 down 
                 SLCO4A1 
               
               
                 −1.1349522 
                 down 
                 −2.5911605 
                 down 
                 −1.056101 
                 down 
                 SNORA1 
               
               
                 1.0827361 
                 up 
                 −1.1856244 
                 down 
                 2.0193295 
                 up 
                 SNORA13 
               
               
                 −1.1392936 
                 down 
                 −2.5419006 
                 down 
                 −1.22043 
                 down 
                 SNORA2A 
               
               
                 −1.1776297 
                 down 
                 −2.339463 
                 down 
                 −1.0959209 
                 down 
                 SNORA42 
               
               
                 −1.0272101 
                 down 
                 −2.0400264 
                 down 
                 1.1371485 
                 up 
                 SNORA6 
               
               
                 −1.5449073 
                 down 
                 −2.4887464 
                 down 
                 −1.3515595 
                 down 
                 SNORA60 
               
               
                 1.0574348 
                 up 
                 −2.9677162 
                 down 
                 1.0178032 
                 up 
                 SNORA62/RPSA 
               
               
                 1.0441421 
                 up 
                 −2.8423023 
                 down 
                 1.2338772 
                 up 
                 SNORA74A 
               
               
                 −1.2188872 
                 down 
                 −3.439569 
                 down 
                 1.0985091 
                 up 
                 SNORA75 
               
               
                 1.1857955 
                 up 
                 −2.4932704 
                 down 
                 1.1226008 
                 up 
                 SNORD14E 
               
               
                 −1.1500319 
                 down 
                 −1.2012677 
                 down 
                 2.0295184 
                 up 
                 SNORD1A 
               
               
                 1.1119288 
                 up 
                 −2.5965233 
                 down 
                 −1.0552726 
                 down 
                 SNORD53 
               
               
                 1.0002517 
                 up 
                 −2.2845662 
                 down 
                 −1.0211544 
                 down 
                 SNORD94 
               
               
                 −1.0808043 
                 down 
                 −1.0452999 
                 down 
                 −2.7743483 
                 down 
                 SNX33 
               
               
                 1.0183113 
                 up 
                 −1.0911404 
                 down 
                 −4.066029 
                 down 
                 SPAG4 
               
               
                 −1.1739895 
                 down 
                 −1.00757 
                 down 
                 −2.1362014 
                 down 
                 SPICE1 
               
               
                 1.0472541 
                 up 
                 −1.1564113 
                 down 
                 3.817899 
                 up 
                 SPINK5 
               
               
                 1.0318233 
                 up 
                 −1.0508822 
                 down 
                 −2.477626 
                 down 
                 SPRY1 
               
               
                 −1.1322684 
                 down 
                 −1.0328805 
                 down 
                 −2.0766609 
                 down 
                 STAMBPL1 
               
               
                 −1.0746213 
                 down 
                 1.0388275 
                 up 
                 −4.0140605 
                 down 
                 STC2 
               
               
                 −1.081674 
                 down 
                 1.0557284 
                 up 
                 −2.0054183 
                 down 
                 SYT7 
               
               
                 1.1072824 
                 up 
                 −1.0533509 
                 down 
                 2.320572 
                 up 
                 TAF9B 
               
               
                 1.1074346 
                 up 
                 −1.0522659 
                 down 
                 2.320647 
                 up 
                 TAF9B 
               
               
                 1.0181974 
                 up 
                 1.1829114 
                 up 
                 2.2189808 
                 up 
                 TBC1D30 
               
               
                 −1.1135601 
                 down 
                 1.2469167 
                 up 
                 −3.272321 
                 down 
                 TCP11L2 
               
               
                 −1.0710702 
                 down 
                 1.0781746 
                 up 
                 −2.2363102 
                 down 
                 TET2 
               
               
                 −1.2701089 
                 down 
                 −1.03623  
                 down 
                 −2.419262  
                 down 
                 TGFB1 g   
               
               
                 1.0019436 
                 up 
                 −1.1744674 
                 down 
                 2.2158334  
                 up 
                 TMCO7 
               
               
                 −1.0518074 
                 down 
                 1.2325256 
                 up 
                 −7.3965917 
                 down 
                 TMEM45A 
               
               
                 −1.1878997 
                 down 
                 1.1371874 
                 up 
                 −2.9050286 
                 down 
                 TMEM45B 
               
               
                 −1.1920087 
                 down 
                 1.2894329 
                 up 
                 −2.3936403 
                 down 
                 TMOD1/TSTD2 
               
               
                 1.0234529 
                 up 
                 −1.0668982 
                 down 
                 −2.1390693 
                 down 
                 TMPRSS3 
               
               
                 −1.0931611 
                 down 
                 1.0688102 
                 up 
                 −2.3202991 
                 down 
                 TNFRSF10D 
               
               
                 1.0020133 
                 up 
                 −1.1098602 
                 down 
                 2.4919987  
                 up 
                 TRIM59 
               
               
                 −1.0013391 
                 down 
                 −1.1124156 
                 down 
                 2.0286796  
                 up 
                 TROAP 
               
               
                 1.0721477 
                 up 
                 1.1957371 
                 up 
                 2.2586193  
                 up 
                 TSEN2 
               
               
                 −1.0218694 
                 down 
                 1.0339891 
                 up 
                 −3.1548517 
                 down 
                 TTYH3 
               
               
                 −1.0063764 
                 down 
                 −1.0644561 
                 down 
                 2.0020242  
                 up 
                 TWISTNB 
               
               
                 −1.1116943 
                 down 
                 −1.1339258 
                 down 
                 −2.000525  
                 down 
                 UACA 
               
               
                 −1.1660498 
                 down 
                 −1.0305872 
                 down 
                 −2.3649898 
                 down 
                 UBASH3B 
               
               
                 −1.0881262 
                 down 
                 1.0408965 
                 up 
                 −2.4548569 
                 down 
                 UPRT 
               
               
                 −1.0898017 
                 down 
                 1.0274819 
                 up 
                 2.0241222  
                 up 
                 UTP15 
               
               
                 −1.038064 
                 down 
                 1.0192441 
                 up 
                 2.0523014  
                 up 
                 UTP20 
               
               
                 −1.0912127 
                 down 
                 1.030388  
                 up 
                 −2.157118  
                 down 
                 VEGFA g   
               
               
                 −1.0415335 
                 down 
                 −1.0828103 
                 down 
                 −6.05876  
                 down 
                 VLDLR 
               
               
                 −1.0228918 
                 down 
                 1.0196353 
                 up 
                 −2.2292318 
                 down 
                 VLDLR/FLJ35024 
               
               
                 −1.1679007 
                 down 
                 −2.2512941 
                 down 
                 1.8234171  
                 up 
                 VTRNA1-1 
               
               
                 1.0775124 
                 up 
                 −1.0424249 
                 down 
                 2.056909  
                 up 
                 WDR12 
               
               
                 1.183166 
                 up 
                 1.0591956 
                 up 
                 2.5667205  
                 up 
                 WDR3 
               
               
                 −1.0831884 
                 down 
                 −1.1266437 
                 down 
                 2.3755276  
                 up 
                 WDR35 
               
               
                 −1.0992746 
                 down 
                 1.0805327 
                 up 
                 −2.1783705 
                 down 
                 WDR45L 
               
               
                 −1.2116722 
                 down 
                 1.0208603 
                 up 
                 −2.6231897 
                 down 
                 WDR52 
               
               
                 −1.2681911 
                 down 
                 −1.0793633 
                 down 
                 −2.2754548 
                 down 
                 WDR52 
               
               
                 −1.1009644 
                 down 
                 1.0549855 
                 up 
                 −3.7621908 
                 down 
                 WSB1 
               
               
                 1.0491763 
                 up 
                 1.0669556 
                 up 
                 2.080929  
                 up 
                 XK 
               
               
                 −1.0340406 
                 down 
                 1.0571353 
                 up 
                 −2.1956234 
                 down 
                 YEATS2 
               
               
                 −1.1708703 
                 down 
                 −1.0094752 
                 down 
                 −2.1953986 
                 down 
                 ZDBF2 
               
               
                 −1.0179691 
                 down 
                 −1.0534668 
                 down 
                 −2.1707454 
                 down 
                 ZNF160 
               
               
                 −1.196344 
                 down 
                 1.0196155 
                 up 
                 −3.2295642 
                 down 
                 ZNF292 
               
               
                 1.0262027 
                 up 
                 −1.0581598 
                 down 
                 −2.5864198 
                 down 
                 ZNF395/FBXO16 
               
               
                 −1.1907156 
                 down 
                 1.0249686 
                 up 
                 −3.4930103 
                 down 
                 ZNF654/CGGBP1 
               
               
                 −1.0689389 
                 down 
                 1.0449277 
                 up 
                 −2.3140717 
                 down 
                 ZSWIM5 
               
               
                 1.1991837 
                 up 
                 −1.0838475 
                 down 
                 2.5001824 
                 up 
                   
               
               
                 1.1989849 
                 up 
                 −1.0842861 
                 down 
                 2.501547  
                 up 
                   
               
               
                 −1.0060402 
                 down 
                 −3.5317602 
                 down 
                 1.2592025 
                 up 
                   
               
               
                 −1.0061597 
                 down 
                 −2.4166691 
                 down 
                 1.3725677 
                 up 
                   
               
               
                 1.0993127 
                 up 
                 −2.1863458 
                 down 
                 1.1684631 
                 up 
                   
               
               
                 −1.2011855 
                 down 
                 1.0950639 
                 up 
                 −2.8855257 
                 down 
                   
               
               
                 −1.1395597 
                 down 
                 −2.5428736 
                 down 
                 1.2404431 
                 up 
                   
               
               
                 1.0368  
                 up 
                 −2.245498 
                 down 
                 −1.1451715 
                 down 
                   
               
               
                 1.0456542 
                 up 
                 −2.5189538 
                 down 
                 1.2004068 
                 up 
                   
               
               
                 1.0580661 
                 up 
                 −1.1550292 
                 down 
                 2.0199893 
                 up 
                   
               
               
                 −1.306305 
                 down 
                 −1.7012253 
                 down 
                 −2.5854821 
                 down 
                   
               
               
                 1.0125278 
                 up 
                 −2.0730047 
                 down 
                 1.3469207 
                 up 
                   
               
               
                 −1.0938246 
                 down 
                 −1.0463859 
                 down 
                 −2.0193262 
                 down 
                   
               
               
                 −1.0510107 
                 down 
                 −1.1346707 
                 down 
                 2.074057  
                 up 
                   
               
               
                 1.1218168 
                 up 
                 1.1611335 
                 up 
                 2.0924993 
                 up 
                   
               
               
                 −1.0498437 
                 down 
                 −2.583383 
                 down 
                 1.0472459 
                 up 
               
               
                   
               
               
                   a [HBS1] vs [Induced] 
               
               
                   b [HBS1] vs [Induced] 
               
               
                   c [HBS2] vs [Induced] 
               
               
                   d [HBS2] vs [Induced] 
               
               
                   e [Vehicle] vs [Induced]  
               
               
                   f [Vehicle] vs [Induced]  
               
               
                   g Hypoxia inducible 
               
               
                   h Pro-angiogenic 
               
            
           
         
       
     
     Example 7 
     Antitumor Activity of HBS 1 in Mouse Xenograft Models 
     A mouse xenograft tumor model was used to assess the in vivo efficacy of HBS 1. The relative plasma stabilities of HBS 1 and linear peptide 3 in mice were first measured. In this experiment, female BALB/c mice were injected with either HBS 1 or peptide 3 at a dose of 1 mg/kg and sacrificed at various time points. Blood was collected and the plasma concentration profiles for HBS 1 and peptide 3 were determined, as shown in  FIG. 21 . While both compounds exhibited a bi-exponential pattern of decay, HBS 1 was retained in plasma at much higher concentrations as compared to peptide 3 during the same time intervals, suggesting that the internally constrained structure of HBS 1 favorably impacts its serum stability. This observation is consistent with the fact that proteases largely bind and cleave peptides in extended conformations. The plasma stability of HBS 1 is also consistent with the published stability of hydrocarbon-bridged helices. 
     The CrTac:NCr-Foxn1 nu  mouse (Taconic, Inc.) was used for efficacy studies. 786-0 renal cell carcinoma of the clear cell type (RCC) cell line was selected, because of its high HIF levels due to a mutation in the VHL gene. Measurable tumors (˜100 mm 3 ) grew in as little as 2-3 weeks after the inoculation of 2×10 6  cells into the flank of the mice. Mice were then separated into the two experimental groups and one group was treated with HBS 1, whereas the second group was not treated (control). 13 mg/kg was estimated to be an acceptable dose, based on the concentration of HBS 1 required for &gt;50% VEGF and LOX mRNA downregulation in cell culture and plasma concentrations of the compounds (vide supra). Tumor sizes were measured in accordance with literature recommendations. Throughout the course of the treatment and at the experiment endpoint, mice treated with HBS 1 had smaller tumors with median tumor volume reduction of 53% as compared to the mice from the control group ( FIG. 22A ). Both control group and mice treated with HBS 1 under this regimen showed no signs of distress or weight loss ( FIG. 22B ). To rule out the possibility that treatment resulted in a reduction of the size of the main tumor but concurrently resulted in an elevated rate of metastasis, as reported with some anti-VEGF therapeutics, the animals were injected with IR-783, a near-infrared contrast agent that targets tumors, circulating tumor cells, and metastases, and imaged from both sides using a small animal imager. The images show no detectable NIR signal within the lymph nodes, brain, or other organs and a significantly reduced signal from the main tumor ( FIG. 22C ). 
     Discussion of Examples 1-7 
     Synthetic inhibitors that block the transactivation domains of transcription factors from contacting their cognate coactivators and programmable small molecules that sequence-specifically inhibit DNA-transcription factor interactions provide powerful strategies for regulating gene expression. This can be especially attractive in targeting cellular pathways that promote oncogenic transformation and typically involve a large number of signaling proteins that ultimately converge on a much smaller set of oncogenic transcription factors. Given the fact that both CBP and p300 regulate multiple signaling pathways, they provide an intriguing opportunity for an effective modulation of the expression of genes involved in cancer progression and metastasis (Vo &amp; Goodman, “CREB-Binding Protein and p300 in Transcriptional Regulation,”  J. Biol. Chem.  276(17):13505-08 (2001), which is hereby incorporated by reference in its entirety). The design strategy described herein involves judicious mimicry of transcription factor fragments that contact p300/CBP to rationally develop artificial regulators of transcription. 
     The present results indicate that synthetic helices that mimic protein subdomains bind their p300/CBP target with high affinity and disrupt the HIF-1αC-TAD-p300/CBP complex in vitro. Importantly, the designed compounds bound the target protein in a predictable manner; the single residue mutant HBS 2 shows an expected weaker affinity for CH1 as compared to HBS 1. The CH1 binding site for HBS 1 was confirmed by NMR HSQC titration experiments. As anticipated based on fluorescence experiments, HBS 1 causes a concentration dependent chemical perturbation shift for the side chain ε-NH of Trp-403. This result supports the design principle that a locked helix can occupy the binding clefts of individual protein α-helices. The in vitro assays showed significant reduction in promoter activity and effective downregulation of the expression of HIF-1α inducible genes responsible for promoting angiogenesis, invasion, and glycolysis. In addition, the HBS 1-mediated transcriptional blockade of VEGF correlates with decreased levels of its secreted protein product, suggesting that compensatory cellular stress response mechanisms such as internal ribosome entry sites (IRES) or mechanisms enhancing protein translation do not affect the observed downregulation in expression. Therefore, reducing the cellular mRNA levels of HIF-1α target genes with HBS 1 could be an effective means of attenuating hypoxia-inducible signaling in tumors. 
     Comparative analysis of the genome-wide effects of HBS 1 and HBS 2 provided additional insights into the ability of the compounds to disrupt transcriptional activity of hypoxia-inducible genes. Despite the similarity in structures, these compounds have a very different impact on the level of expression of hypoxia-inducible genes and show distinct genome-wide effects. Treatment with HBS 1 affects 122 genes (less than 0.5% of the entire transcriptome) at a fixed 1.1-fold threshold, with 92 hypoxia-inducible genes being downregulated. Despite the fact that HBS 2 has a similar genome-wide impact at the same threshold, it does not affect a majority of hypoxia-inducible genes. Because many biological responses are threshold-based, the observed decrease in transcriptional activity of primary hypoxia-inducible genes could have pronounced downstream effects on the levels of protein products of hypoxia-inducible transcription. 
     To assess the in vivo potential of HBS 1, murine tumor xenografts derived from the renal cell carcinoma of the clear cell type (RCC) were treated with the compound. After five injections of HBS 1, the median tumor volume was reduced by 53% in the treated group. Importantly, the HBS 1 treatment did not cause measurable changes in animal body weight or other signs of toxicity in tumor-bearing animals, nor increase the metastasis rate. 
     Taken together, the results reported herein support the hypothesis that designed protein domain mimetics can provide valuable tools for probing the mechanisms of transcription. Because the p300/CBP pleiotropic coactivator system interacts with diverse transcription factors, it represents an excellent model system to assess the specificity of designed synthetic ligands in gene regulation. The strategy described herein provides a foundation for the development of novel genomic tools and transcription-based therapies. 
     Although preferred embodiments have been depicted and described in detail herein, it will be apparent to those skilled in the relevant art that various modifications, additions, substitutions, and the like can be made without departing from the spirit of the invention and these are therefore considered to be within the scope of the invention as defined in the claims which follow.