bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2459: Discovery of small molecule TAK1 inhibitors with antiproliferative activity in cell lines derived from hematological malignancies.
Authors: Toader Dorin , Saeh Jamal C. , Guan Nin , Powell Francoise , Chen Raymond , Reimer Corinne , Byth Kate 
Published: August 2014

Abstract
Transforming growth factor β-activated kinase 1 (TAK1), a member of the MAPKKK family, is a key mediator of proinflammatory and stress signaling. It was shown previously that inhibition of TAK1 via the use of siRNA or small-molecule kinase inhibitors can inactivate NF-κB, down-regulate p38, and activate the intrinsic caspase pathway, resulting in profound induction of apoptosis. Herein we report the discovery of 5-fluoro-4-(imidazo[1,2-b]pyridazin-3-yl)-N-phenylpyrimidin-2-amines as TAK1 ATP competitive small molecule inhibitors. These compounds inhibit the kinase activity of TAK1 in vitro with low nanomolar potency. Evidence is presented that supports a mechanism of action consistent with inhibition of TAK1 kinase activity within the NF-κB pathway. Optimization of potency and selectivity for this series from hit to lead will be discussed, including the structure-based design and crystallographic determination of the binding mode. The outcome of efforts aimed at improving the in vivo pharmacokinetics of compounds is described. Results of kinase selectivity profiling for both an in vitro probe compound - AZ TAK1 - and an in vivo probe compound will be presented. Furthermore, we report low nanomolar antiproliferative activities in cell lines derived from Haematological Malignancies for these compounds. This cellular activity profile is suggesting that TAK1 inhibition presents therapeutic potential in Haematological Cancers.
Citation Format: Dorin Toader, Jamal C. Saeh, Nin Guan, Francoise Powell, Raymond Chen, Corinne Reimer, Kate Byth. Discovery of small molecule TAK1 inhibitors with antiproliferative activity in cell lines derived from hematological malignancies. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2459. doi:10.1158/1538-7445.AM2013-2459
Abstract 2463: Discovery of imidazo[1,5-a]pyrazine derived potent, selective and orally bioavailable ACK1 inhibitors.
Authors: Jin Meizhong , Wang Jing , Kleinberg Andrew , Kadalbajoo Mridula , Siu Kam W. , Cooke Andrew , Bittner Mark , Yao Yan , Thelemann April , Ji Qunsheng , Bhagwat Shripad , Mulvihill Kristen M. , Rechka Josef A. , Pachter Jonathan A. , Crew Andrew P. , Epstein David , Mulvihill Mark J. 
Published: August 2014

Abstract
Activated Cdc42-associated kinase (ACK1) is a non-receptor tyrosine kinase originally identified by virtue of its binding to GTP-bound small GTPase Cdc42. Considerable attention has been paid to ACK1’s involvement in cancer in recent years. For example, gene amplification and over-expression of ACK1 were found in multiple cancers including lung, ovarian and prostate cancers and were associated with poor prognosis and metastatic phenotypes. Activated ACK1 has been shown to phosphorylate and activate androgen receptor function and to promote the progression of prostate cancer. More recently, activated ACK1 was found to phosphorylate and promote the activation of Akt, a protein kinase that plays a central role in growth, proliferation and cell survival in various cancers. Taken together, these literature data suggest that ACK1 is a potential target for cancer treatment. Several series of ACK1 inhibitors have been previously disclosed in literature. Unfortunately, compounds from these series suffer from poor oral pharmacokinetic (PK) properties which have prevented them from being utilized further for in vivo studies. Therefore, there is a clear need for potent, selective and orally bioavailable small molecule ACK1 inhibitors to further probe its role in cancer, both in the in vitro and in vivo setting. This report describes the medicinal chemistry effort towards a series of novel imidazo[1,5-a]pyrazine derived inhibitors of ACK1. Virtual screening led to the discovery of the initial hit, and subsequent exploration of structure-activity relationships and optimization of drug metabolism and pharmacokinetic properties led to the identification of potent, selective and orally bioavailable ACK1 inhibitors.
Citation Format: Meizhong Jin, Jing Wang, Andrew Kleinberg, Mridula Kadalbajoo, Kam W. Siu, Andrew Cooke, Mark Bittner, Yan Yao, April Thelemann, Qunsheng Ji, Shripad Bhagwat, Kristen M. Mulvihill, Josef A. Rechka, Jonathan A. Pachter, Andrew P. Crew, David Epstein, Mark J. Mulvihill. Discovery of imidazo[1,5-a]pyrazine derived potent, selective and orally bioavailable ACK1 inhibitors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2463. doi:10.1158/1538-7445.AM2013-2463
Abstract 2464: Flavone derivatives as small-molecule probes of cytochrome P450 enzymes: Inhibitory activity and selectivity.
Authors: Liu Jiawang , Taylor Shannon , Dupart Patrick , Arnold Corey , Foroozesh Maryam 
Published: August 2014

Abstract
Cytochrome P450 enzymes are the most important enzymes involved in the conversion of environmental procarcinogens such as polycyclic aromatic hydrocarbons (PAHs) from fuels, cigarette smoke, and charcoal-grilled foods into carcinogenic species. These carcinogenic species have the potential to bond to cellular macromolecules such as DNA and can lead to cancer formation. Therefore, selectively inhibiting certain P450 enzymes involved in carcinogenesis is a potential approach to cancer prevention. To investigate the 3D-structural features of the active site cavities of our target P450s, our approach in this project is to use the natural P450 substrate, flavone, as a lead compound. Here we report the synthesis of six novel flavonoids (5,6-pyranflavone, 6,5-pyranflavone, 7,8-pyranflavone, 2’,3’-pyranflavone, 3’,2’-pyranflaovne, and 4’,3’-pyranflavone) and the evaluation of their inhibitory activities, mechanisms of action, and selectivity towards P450 enzymes 1A1, 1A2, 2A6, and 2B1. All of these target compounds were found to be competitive inhibitors of these P450 enzymes. A high inhibitory activity represents a high affinity between the compound and the enzyme. Our data show that the α-naphthoflavone-like flavone derivative, 7,8-pyranflavone, has a high affinity for P450 1A2 (IC50: 0.05 μM), and a relatively low affinity for P450 1A1 (IC50: 0.25 μM). On the contrary, β-naphthoflavone-like flavone derivatives, 5,6-pyranflavone and 6,5-pyranflavone, show higher affinities for P450 1A1 compared to P450 1A2. However, none of these three compounds shows any inhibitory activity towards P450s 2A6 and 2B1. Interestingly, the C-ring modified derivatives (2’,3’-pyranflavone, 3’,2’-pyranflaovne, and 4’,3’-pyranflavone) have relatively low inhibitory activities toward the P450s 1A1 and 1A2, while showing a weak inhibition of P450 2B1 (IC50s: ca. 7.0 μM). These structural data suggest that the length of the P450 1A1 active site cavity is probably longer than that of P450 1A2, while the width of the P450 1A2 active site cavity may be larger than that of P450 1A1. Further studies of 7,8-pyranflavone, 5,6-pyranflavone, and 6,5-pyranflavone will provide us with more detailed structural information about the target P450 enzymes.
Citation Format: Jiawang Liu, Shannon Taylor, Patrick Dupart, Corey Arnold, Maryam Foroozesh. Flavone derivatives as small-molecule probes of cytochrome P450 enzymes: Inhibitory activity and selectivity. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2464. doi:10.1158/1538-7445.AM2013-2464
Abstract 2467: Development of new N-Arylbenzamides as STAT3 dimerization inhibitors.
Authors: Lawrence Nicholas J. , Pireddu Roberta , Ge Yiyu , Urlam Murali K. , Zhang Xiaolei , Sun Ying , Lawrence Harshani R. , Guida Wayne C. , Sebti Said 
Published: August 2014

Abstract
The association of aberrant STAT3 activation with many types of human malignancies and solid tumors makes STAT3 an attractive molecular target for the development of novel cancer therapeutics. STAT3 dimerization via two reciprocal phosphotyrosine (pTyr)-Src-homology 2 (SH2) interaction is required for its binding to specific DNA-response elements in the promoters of target genes. This dimerization process offers a potentially selective way to directly target STAT3. Nevertheless the design of small molecules capable of disrupting protein-protein interactions remains a significant challenge to medicinal chemistry. We describe the development of a new class of small molecule capable of disrupting the STAT3:STAT3 protein-protein interaction. We identified the STAT3 inhibitor S3I-201 (NSC-74859) from the NCI chemical collection by using structure-based virtual screening with a model based on the X-ray crystal structure of the STAT3β homodimer. We developed a series of phosphonic and salicylic acids based on the structure of S3I-201 incorporating an N-arylbenzamide scaffold. The series of phosphonic and salicylic acids with a shorter amide linker lacking the O-tosyl group has improved STAT3 inhibitory activity [as measured by a competitive, fluorescence-polarization (FP)-based assay]. The equivalent in vitro potencies observed by the replacement of phosphonic acid moiety of with 5-amino-2-hydroxybenzoic acid group validates 5-amino-2-hydroxybenzoic acid as a phosphotyrosine mimic in this series. The binding mode of selected compounds, as predicted by molecular modeling, will be discussed. Our docking studies indicated that the phosphonic and salicylic acid groups interact in the pTyr-705 binding site in a broadly similar manner, while the other substituents occupy the STAT3 pY+1 and pY-X hydrophobic pockets. One of the most potent compounds in vitro (in the FP assay) inhibits STAT3 dimerization in intact cells and suppresses malignant transformation in human cancer cells that depend on STAT3. The in vitro and cell based potency of the N-arylbenzamides warrants further development of this scaffold as STAT3 inhibitors.
Citation Format: Nicholas J. Lawrence, Roberta Pireddu, Yiyu Ge, Murali K. Urlam, Xiaolei Zhang, Ying Sun, Harshani R. Lawrence, Wayne C. Guida, Said Sebti. Development of new N-Arylbenzamides as STAT3 dimerization inhibitors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2467. doi:10.1158/1538-7445.AM2013-2467
Abstract 2472: Small-molecule-induced reactivation of mutant p53 in cancer cells.
Authors: Liu Xiangrui , Wilcken Rainer , Joerger Andreas , Chuckowree Irina , Spencer John , Fersht Alan 
Published: August 2014

Abstract
The tumour suppressor p53 inhibits tumour growth by induction of cell cycle arrest, apoptosis or senescence. However, p53 mutations occur frequently in human tumours. About one-third of the mutations lower the melting temperature of the protein and cause rapidly unfolds at body temperature. The p53 cancer mutant Y220C is an excellent paradigm for rescuing the function of conformationally unstable p53 mutants because it has a unique surface crevice that can be targeted by small-molecule stabilizers. Through biophysical and cell-based screening, we identified a compound, PK7088, which binds to the Y220C mutant with a dissociation constant of 140 μM. The binding mode of this compound class was determined by X-ray crystallography. In cancer cells carrying the Y220C mutant, PK7088 increased the amount of folded mutant protein with wild-type like conformation, as monitored by immunofluorescence, and restored its transcriptional functions. It induced p53-Y220C-dependent growth inhibition, cell-cycle arrest and apoptosis. This was confirmed by p53 silencing. Most notably, PK7088 increased the expression levels of p21 and the proapoptotic NOXA protein. PK7088 worked synergistically with Nutlin-3 on up-regulating p21 and NOXA expression, whereas Nutlin-3 on its own had no effect, consistent with its mechanism of action. PK7088 also restored non-transcriptional apoptotic functions of p53 by triggering nuclear export of BAX to the mitochondria. These findings provide novel insights into p53 mutant reactivation and may facilitate the development of more potent and selective small-molecule drugs for specific mutant p53 rescue.
Citation Format: Xiangrui Liu, Rainer Wilcken, Andreas Joerger, Irina Chuckowree, John Spencer, Alan Fersht. Small-molecule-induced reactivation of mutant p53 in cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2472. doi:10.1158/1538-7445.AM2013-2472
Abstract 2473: Fragment-based discovery of inhibitors of replication protein A protein-protein interactions.
Authors: Waterson Alex G. , Patrone James D. , Kennedy J. Phillip , Pelz Nicholas F. , Frank Andreas O. , Vandgamudi Bhavatarini , Feldkamp Michael D. , Souza-Fagundes Elaine M. , Rossanese Olivia W. , Chazin Walter J. , Fesik Stephen W. 
Published: August 2014

Abstract
Replication Protein A (RPA) is a heterotrimeric protein that binds to and protects ssDNA and plays an integral role in initiating the cellular response to DNA damage. This response is mediated via protein-protein interactions between a basic cleft on the RPA70N subunit and a number of protein partners, including ATRIP, Rad9, Mre11, and p53. RNAi against RPA has shown an expected toxicity against cancer cell lines, possibly due to abrogation of the ssDNA binding function of RPA. Specific disruption of the protein-protein interactions between the RPA07N subunit and its binding partners has the potential to produce a more selective cytotoxic response in cancer cells. To more accurately dissect the therapeutic relevance of disrupting only the protein-protein interaction functions of RPA, we sought to discover potent small molecule probes that bind to the basic cleft of RPA70N.
Inhibition of protein-protein interactions is considered a difficult task. An NMR-based fragment screen has identified more than 130 fragment molecules that bind to the RPA70N protein-protein interaction cleft with affinities that range from 500 μM to 2 mM and corresponding ligand efficiencies from 0.18 to 0.30. Selected fragments, representing several distinct chemotypes, have been optimized for binding to the protein. Using X-ray crystallography, the binding modes of these fragments have been defined. Fragments were found to bind primarily to two main sites within the basic cleft of RPA70N. Additional structure-guided optimizations have been carried out and ternary co-crystal structures have been generated to guide fragment linking strategies. Together, these activities have led to the creation of multiple lead series of inhibitors of the RPA:ATRIP interaction, with binding affinities improved by several fold over the initial fragments. The SAR and biological activities of the fragments and lead compounds will be discussed.
Citation Format: Alex G. Waterson, James D. Patrone, J. Phillip Kennedy, Nicholas F. Pelz, Andreas O. Frank, Bhavatarini Vandgamudi, Michael D. Feldkamp, Elaine M. Souza-Fagundes, Olivia W. Rossanese, Walter J. Chazin, Stephen W. Fesik. Fragment-based discovery of inhibitors of replication protein A protein-protein interactions. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2473. doi:10.1158/1538-7445.AM2013-2473
Abstract 2474: Synthesis and antiproliferative activity of novel 17β-acetyl-testosterone-7α-platinum(II) hybrids designed for the treatment of human prostate cancer.
Authors: Fortin Sébastien , Brasseur Kevin , Morin Nathalie , Asselin Éric , Bérubé Gervais 
Published: August 2014

Abstract
Prostate cancer is a major public health problem worldwide. In the United-States, prostate cancer is ranked first of all new cancer cases diagnosed in men and it is the second most lethal cancer. Antiandrogens are normally used in clinic to slow down the progression of androgen-sensitive (AR+) prostate cancer inducing prolonged remission without definite cure. In general, 10 years after the initial treatment of early prostate cancers, 19% of patients will experience local tumor progression, 15% distant metastases and 10% will die. Furthermore, advanced prostate cancers quickly (18 to 24 months) become androgen-insensitive (AR-) and antihormone therapy becomes ineffective. At this point, the median survival of approved drug combination treatments is then under 20 months. Consequently, the search for new, more selective and efficient treatments is still a subject of intense research.
To that end, we used the natural tropism of testosterone for prostate tissues to target platinum(II) complexes to prostate cancer cells. The platinum complexes were linked to the 7α position on testosterone as it is located between the 3-carbonyl and 17-hydroxyl groups involved in key hydrogen bonds essential for androgen receptor interactions. L- and D-2-pyridylalanine, L-histidine and L-4-thiazolylalanine derivatives were linked to 17β-acetyl-testosterone selected to chelate platinum(II). Four new amino acid platinum(II) complexes were prepared (compounds 1a-1d), characterized and evaluated for their antiproliferative activity on LNCaP (AR+), PC3 (AR-) and DU145 (AR-) human prostate adenocarcinoma cancer cell lines.
The new testosterone-platinum(II) complexes exhibited antiproliferative activities at the micromolar level on all prostate cancer cell lines tested. Structure-activity relationships show that the stereochemistry of amino acids (compounds 1a, b) does not affect the antiproliferative activity. Moreover, the replacement of a pyridinyl moiety by an imidazolyl group (compound 1c) decreased the activity by up to 10 fold whereas the replacement by a thiazolyl group (compound 1d) showed an antiproliferative activity between 2.5 to 8.0 times higher than that of cisplatin.
The innovative design and the significant activity of our testosterone-platinum(II) complexes toward AR+ and AR- prostate cancer cells suggest that they might be useful for treatment of advanced prostate cancers.
Citation Format: Sébastien Fortin, Kevin Brasseur, Nathalie Morin, Éric Asselin, Gervais Bérubé. Synthesis and antiproliferative activity of novel 17β-acetyl-testosterone-7α-platinum(II) hybrids designed for the treatment of human prostate cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2474. doi:10.1158/1538-7445.AM2013-2474
Abstract 2476: Synthesis of novel aza-podophyllotoxins derivatives substituted at ring-A and their activities on NCI-60 human tumor cell line.
Authors: Kumar Ajay , Kumar Vineet , Malhotra Sanjay V. , Antonio Alegria E. 
Published: August 2014

Abstract
Podophyllotoxin is a major cytotoxic constituent of several members of Podophyllum peltatum species. The semisynthetic derivatives namely etoposide, etopophos and teniposide have been developed from podophyllotoxin and are currently used in clinic for the treatment of several human tumors since five decades. Synthesis of podophyllotoxin is not feasible so far and due to this reason structural modification of podophyllotoxin could not be explored very well. The structural complexity of podophyllotoxin, arising from the presence of four stereogenic carbons in ring C has restricted most of the structural activity relationship (SAR) studied by derivatization of the parent natural product rather than by de novo multi-step chemical synthesis. In past we have developed various heterocyclic analogues of podophyllotoxin derivatives. Owing to their promising activity against 60 cell lines at NCI, we are actively engaged in developing new library of N-hydroxyethyl-4-aza-didehyropodophyllotoxin derivatives. A new library of aza-podophyllotoxin derivatives substituted at ring-A has been developed and followed by a screen of in vivo activity using a panel of tumor hollow-grafts implanted in mice consisting of breast (MDA-MB-231), non-small lung (NCI-H23 and NCI-H522), colon (SW-620 and COLO 205), melanoma (UACC-62, MDA-MB-435 and LOXIMVI), ovarian (OVCAR-5 and OVCAR-3) and CNS (U251 and SF-295) cell lines. These new compounds found to have comparatively good activity against colon and cancer lines.
Citation Format: Ajay Kumar, Vineet Kumar, Sanjay V. Malhotra, Alegria E. Antonio. Synthesis of novel aza-podophyllotoxins derivatives substituted at ring-A and their activities on NCI-60 human tumor cell line. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2476. doi:10.1158/1538-7445.AM2013-2476
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract 2478: Novel tyrosine derivatives of temozolomide active against breast cancer cell lines.
Authors: O'Sullivan Jordan Kiefer , Helphrey Taylor R. , Laim Johnny , Louie Maggie C. , Carranza Maria Graciela 
Published: August 2014

Abstract
A series of L- and D-tyrosine derivatives of temozolomide (TMZ) was synthesized and evaluated as potentially improved anticancer agents against breast cancer cell lines. TMZ is a well tolerated, broad spectrum oral alkylating agent that crosses the blood–brain barrier. It has demonstrated activity against glioma and melanoma, as well as preclinical activity against breast cancer. Recent studies have shown the effectiveness of combining alkylating agents with the amino acid tyrosine, yielding analogs with significantly improved in vitro anticancer activity when compared with the parent compound. Following from this, we seek to improve the efficacy of TMZ by chemically modifying the C-8 position of the imidazotetrazine to include L- and D-tyrosine adducts attached either directly or via a linker of varying size. The novel TMZ derivatives were synthesized in good yields through efficient peptide synthesis methods. The anticancer efficacy of the derivatives was evaluated over several hormone-dependent and hormone-independent (ER+ and ER-) breast cancer cell lines. Preliminary results show that at a concentration of 2 x 10−5 M the novel derivatives display at least a 20% greater in vitro growth inhibitory activity when compared to TMZ, particularly in hormone-dependent MCF-7 breast cancer cell line. Structure–activity relationship (SAR) analysis suggests the influence of both the length of the linker and the stereochemistry of the tyrosine adduct on the anticancer activity of the derivatives. Further investigation will reveal if interaction with hormone-related receptors is involved in the mechanism of action of the newly synthesized derivatives.
Citation Format: Jordan Kiefer O'Sullivan, Taylor R. Helphrey, Johnny Laim, Maggie C. Louie, Maria Graciela Carranza. Novel tyrosine derivatives of temozolomide active against breast cancer cell lines. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2478. doi:10.1158/1538-7445.AM2013-2478