bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 733: Synthesis and biological evaluation of inhibitors of Rho protein kinase
Authors: Pireddu Roberta , Sun Nan N. , Yu Huidong , Sung Shen-Shu , Sebti Said M. , Lawrence Nicholas J. 
Published: February 2011

Abstract
Rho GTPases are small G-proteins which play a critical role in signaling pathways and control cell growth and division. Rho-associated protein kinase (known as ROCK or Rho kinase) is a Ser/Thr protein kinase activated by GTP-bound Rho and phosphorylates important signalling proteins. Rho/ROCK mediated signalling pathways are implicated in cell morphology, moltility, smooth muscle contraction, formation of stress fiber, focal adhesion, cell transformation and cytokineses. ROCKs have been subject to growing attention, having been implicated in a range of therapeutic areas including cancer. Further, the pharmacological inhibition of ROCKs has been suggested as a promising strategy in the prevention of cell invasion, a central event in the process of metastasis.
We describe the identification of potent ROCK inhibitors from data mining of the Molecular Libraries Screening Center Network (MLSCN) data available through PubChem and in-house HTS screening. Libraries of compounds have been designed to aid the hit-to-lead process and probe structure activity relationships. Molecular modeling and crystallography have been used to aid the design of potent ROCK inhibitors. Compounds were first assessed for in vitro ROCK1 inhibitory activity using a Z-lyte kinase assay. Selected compounds were also screened against the isoform ROCK2. Selectivity trends will be discussed. The overall process has led to the improvement of activity of compounds from high micromolar activity to low nanomolar activity. Structure activity relationship studies led to the identification of highly potent and cell-permeable analogues that were shown to inhibit selected substrates of ROCK such as MYPT1 in cell assays and are the subject of ongoing antitumor studies.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 733.
Abstract 742: Development of novel naphthalimide derivatives as potential melanoma therapeutics
Authors: Sk Ugir Hossain , Gowda A.S. Prakasha , Gimbor Melissa A. , Gowda Raghavendra , Robertson Gavin P. , Spratt Thomas E. , Yun Jong K. , Amin Shantu , Sharma Arun K. 
Published: February 2011

Abstract
Over the years, several naphthalimide analogs with varying efficacy have been reported as having promising anti-cancer properties. Some analogs such as mitonafide, a tolemerase inhibitor, have shown an interesting antitumor activity both preclinically and in phase I and phase II clinical trials. However, it suffers from severe toxicity issues, especially central nervous system (CNS) toxicity. Because of toxicity issues, mitonafide could only be delivered by i.v. infusion, and still CNS toxicity is a major issue. This problem was overcome by adapting a delivery strategy of 5 days continuous infusion, but this regimen was not effective in NSCLC or colorectal cancer patients, while still having severe myelotoxicity in the latter case. These observations warranted optimization of mitonafide structure by adding appropriate functional groups that could help reduce systemic toxicity, while keeping the key naphthalimide moiety intact. We hypothesized that incorporation of functional groups such as isothiocyanate group which is present various naturally occurring agents found in cruciferous vegetables would enhance the bioavailability and reduce systemic toxicity levels. By analogy, isoselenocyanate group which has recently been shown by us to follow a similar mechanism with enhanced potency was also introduced. Furthermore, we also synthesized a series of mitonafide analogs with functional alterations such as thiourea and selenourea in place of N,N-dimethyl functionality in mitonafide, with or without nitro substitution. Interestingly, all the sulfur analogs [IC50 (72 h): 2-9 uM] were more cytotoxic than their corresponding selenium derivatives [IC50 (72 h): 11-24 uM], as observed by the MTS assay in various human melanoma cell lines. This was in sharp contrast to our earlier studies, where isosteric selenium analogs were more effective in killing multiple cancer cells and about 3 times more effective in inhibiting melanoma tumor development. Furthermore, the sulfur analogs effectively induced apoptosis in UACC 903 human melanoma cells. Nitro substitution or increase in alkyl chain length did not seem to make any significant difference in the activity of these compounds. Though the IC50 values were 2-4 times lower for mitonafide [IC50 (72 h): 1-2 uM] compared to novel isothiocyante or thiourea derivatives, these new derivatives were well tolerated when injected i.p. in mice everyday for a month. The new naphthalimide derivatives thus hold solid promise as melanoma therapeutics.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 742.
Abstract 743: Assessment of novel tyrosine-chlorambucil hybrid molecules on a panel of breast, ovarian, and uterine cancer cell lines
Authors: Leblanc Valerie , Descoteaux Caroline , Parent Sophie , Berube Gervais , Asselin Eric 
Published: February 2011

Abstract
Site-specific drug targeting is the suject of very intense research to improve selectivity and therapeutic index towards breast and gynecological (ovarian and endometrial) cancers. Recently, our group have designed and synthesized a new class of amino acid-linked nitrogen mustard hybrids. The new hybrids are designed to mimic 17β-estradiol in order to target ERα-overexpressing tumor cells. For this purpose, tyrosine was used as the starting material to which chlorambucil was added to construct several tyrosine-chlorambucil hybrids. The phenol group of the tyrosine moiety imitates the phenol group of estradiol. Thus, the new hybrids are designed to target the estrogen receptor and to direct the cytotoxic moiety to hormone-dependent cancer cells. Chlorambucil is a slow acting nitrogen mustard mainly used in chronic lymphocytic leukemia and primary macroglobulinemia. It is also useful in treating lymphosarcoma and Hodgkin's disease. Two different families of hybrids were made. The aim of the study was to determine the cytotoxic effects of these unique molecules using estrogen dependent (ER+; Ishikawa, Ovcar-3, MCF-7, ZR-75-1) and independent (ER-; Hec-1A, A2780, MDA-MB-468) human breast, ovarian and uterine cancer cells. The results show the possible interactions of the two families of hybrids with ERα as demonstrated by molecular modeling. The biological activity of these compounds was evaluated in vitro using the MTT cell proliferation assay. Depending of the different hybrids tested the novel compounds generally possess up to 10 time higher biological activities when compared to the parent drug. Given the significant cytotoxic activity of these original tyrosine-chlorambucil hybrids, we believe that they represent a promising alternative treatment for hormone-dependent female cancers.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 743.
Abstract 745: Structure-activity relationship study of the novel aspirin-based anticancer compounds
Authors: Joseph Stancy J. , Nie Ting , Johnson Francis , Gupta Ramesh , Rigas Basil 
Published: February 2011

Abstract
We performed a structure-activity relationship (SAR) study of novel derivatives of aspirin (ASA) which show strong anticancer activity in vitro and in vivo. We synthesized a series of ASA-based benzyl esters (ABEs) and evaluated their inhibitory activity against human colon (HT-29 and SW480) and pancreatic cancer cell lines (BxPC-3 and MIA PaCa-2). The ABEs that we studied largely comprise organic benzyl esters bearing an ASA or acyloxy group (X) at the meta or para position of the benzyl ring and one of four different leaving groups. The nature of the salicyloyl/acyloxy function, the leaving group, and the additional substituents affecting the electron density of the benzyl ring, all were influential determinants of the cancer cell growth inhibitory activity of each ABE. Positional isomerism also played a significant role in this effect. Our SAR study provides an insight into the biological properties of this novel class of compounds and underscores their potential as anticancer agents.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 745.
Abstract 749: Predicting and improving potential anticancer proteomimetics with computational modeling
Authors: Chen Kevin 
Published: February 2011

Abstract
In this work, computational approaches were used to investigate peptides for possible anticancer drug applications. Programmed cell death (apoptosis) is an important cellular process. Its malfunction can lead to cancer and other diseases. Apoptosis is regulated by both pro-death and pro-survival proteins. An over expression of pro-survival proteins can trigger cancer progression and poor chemotherapy response. A class of recently designed proteo-mimetics may help trigger death in cancer cells by hindering expression of certain pro-survival proteins.
The Deep View program and the Swiss Model server were used to model interactions between pro-survival Bcl-xl protein and pro-death Bim protein. First, all binding residues of the Bcl-xl-Bim complex were identified. Bim residues were then systematically mutated. The goal was to study the significance of side chain groups for the complex formation. The changes in binding free energy, caused by the mutations, were calculated.
Most mutations had a negligible influence on Bcl-xl-Bim interactions.
However, some mutations produced additional bonds with Bcl-xl. Several residue substitutions led to minimization of free energies. Most of these residues were binding either at the original Bcl-xl binding or in its vicinity. The obtained minimum-energy peptides suggested putative proteomimetics that could form strong bonds with Bcl-xl. These could cause Bim to dislodge from the Bcl-xl binding site and thus stimulate apoptosis. The potential of the mutated peptides to hinder tumor cells’ survival is discussed.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 749.
Abstract 751: Synthesis of irofulven analogs
Authors: Kelner Michael J. , McMorris Trevor C. 
Published: February 2011

Abstract
Irofulven (NSC 683863), a semi-synthetic analog of the fungal product illudin S, that has been evaluated in a variety of phase I and II clinical trials. Promising results were noted in clinical trials against a variety of solid cancers including colon, sarcoma, prostate, liver, ovarian and pancreas. Irofulven in a randomized phase IIB trial increased median overall lifespan in patients with metastatic taxane-refractory prostate cancer [HR = 0.69]. As irofulven was the first member of the acylfulvene class of agents to be created, we synthesized several hundred analogs for further testing. Modifications were specifically made to 7 sites of the irofulven molecule including the cyclopropane ring, the chiral center, the carbonyl group, the tertiary hydroxyl site, and several nucleophilic sites. Modifications at several sites completely eliminated both the cytotoxicity and antitumor activity of the analog. Analogs with modifications at one site retained cytotoxic activity, as well as in vivo toxicity in rodents, but surprisingly eliminated antitumor activity in xenograft models. Analogs in which the tertiary hydroxyl group of irofulven was replaced with specific functional groups were noted to have an increase in tumor selectivity as noted by both cell culture and xenograft studies. Specific functional groups noted to be favorable for increased activity included carbamate, sulfonamide, and urea moieties. Additional derivatives of each of these specific functional groups were synthesized and tested in a variety of cell culture and xenograft studies including multidrug resistant models. These studies identify molecular sites critical for the antitumor activity of acylfulvenes, as well as identify promising new analogs for further investigation.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 751.
Abstract 758: Development of novel anticancer agents based on fusarochromanone
Authors: Mahdavian Elahe , Buckley Bonnie , Sermons Matthew , Clifford John L. , Furmanski Brian D. , Salvatore Brian A. 
Published: February 2011

Abstract
Cancer is the leading disease-related killer in the US, and therefore there is tremendous need for effective new chemotherapeutic treatments. The ultimate goal of this research project is to discover and develop novel chemotherapeutic agents of more potency and less toxicity for treatment of cancer patients. Increasingly, researchers are attempting to optimize bioactive natural products in order to enhance their efficacy and minimize their toxicity. The primary goal of this research is to develop novel anti-cancer agents based on fusarochromanone (FC101a), a natural mycotoxin with potent anti-angiogenic and direct anti- tumor activity. Like most other bioactive natural compounds, the potency of FC101a is compromised in-vivo, suggesting rapid metabolism and/or poor bioavailability and distribution. Clearly, further development of FC101a as a chemotherapeutic drug requires that we complete its total synthesis, as well as the synthesis of a series of structural analogs that may show greater in-vivo potency. The creation of the parent FC101a and its analogs will allow for the analysis of quantitative structure/activity relationships (QSAR), using both in-vitro cellular and in-vivo animal models of tumorigenesis.
Our research group has already synthesized a series of simplified FC101 analogs without the side chain, and we have conducted preliminary assays to determine the effect of these analogs on in-vitro cancer-cell viability and proliferation. In contrast to the parent compound, most of these new synthetic analogs that lack the side chain found in the natural product have increased cell viability and proliferation for all cell lines tested. This sharp contrast in activity indicates that the FC101 side chain is required for the anti-cancer and angiogenic activity of this molecule. Although the stimulation of proliferation may have profound applications (e.g., the stimulation of stem cell growth), we are focusing our current research efforts on the natural product itself as well as new side chain analogs that may find direct application in the treatment of cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 758.
Abstract 760: Sensitizing tumors to chemotherapy by inhibition of gamma-glutamyl transpeptidase
Authors: LaChapelle Stephanie , Cook Paul F. , Hanigan Marie H. 
Published: February 2011

Abstract
Tumors that express the cell surface enzyme gamma-glutamyl transpeptidase (GGT) have increased resistance to chemotherapy and radiation. GGT cleaves the gamma-glutamyl bond of extracellular glutathione, initiating the cleavage of glutathione into glutamate, cysteine and glycine. Glutathione can not be taken up intact by tumor cells. Cleavage of extracellular glutathione increases the supply of cysteine to the cell, which is essential to increasing intracellular glutathione levels. Glutathione detoxifies chemotherapy drugs, and elevated levels of intracellular glutathione can block apoptosis. We are developing inhibitors of GGT that can be used to sensitize tumors to therapy. The standard assay for GGT activity uses p-nitroanilide derivatives as substrates, millimolar concentrations of dipeptides as acceptors and is buffered at pH 8.6. Under these assay conditions several groups of investigators have shown that GGT cleaves the gamma-glutamyl bond of the substrate and transfers the gamma-glutamyl group to an acceptor by a Ping-Pong mechanism. However, the standard assay for GGT activity does not measure the reaction catalyzed by GGT in vivo. We have assayed GGT activity under physiologic conditions. We have found that some compounds that inhibit GGT activity in the standard reaction do not inhibit under physiologic conditions. Our data reveal that, at physiologic pH and osmolarity with reduced concentrations of acceptor, the enzyme does cleave the gamma-glutamyl bond by a Ping-Pong mechanism, but hydrolysis of the intermediate of the gamma-glutamyl enzyme intermediate is significant, and competition between water and the peptide acceptor for the intermediate makes it appear Sequential. Several compounds that inhibit GGT in the standard assay actually accelerate activity as the concentration of the acceptor is reduced to physiologic levels. To identify inhibitors that are optimized for clinical use, we have developed an assay that evaluates GGT cleavage of glutathione, the physiologic substrate, at physiologic pH and osmolarity. We are using our previously reported inhibitor OU749 and other lead compounds to further characterize the physiologic GGT reaction and to identify essential substructural components for inhibition of GGT activity.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 760.
Abstract 761: The development of cell permeable Shp2 PTP inhibitors
Authors: Lawrence Harshani R. , Chen Liwei , Pernazza Daniele , Scott Latanya , Ren Yaun , Luo Yunting , Wu Xin , Shen-Shu Sung , Guida Wayne , Sebti Said M. , Lawrence Nicholas J. , Wu Jie 
Published: February 2011

Abstract
Protein tyrosine phosphorylation affects cellular activities that control tumor growth and progression. Protein tyrosine phosphorylation, a key regulatory process of signal transduction pathways, is controlled by the action protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs). Kinases are now a clinically proven anticancer drug target. The development of PTP inhibitors is, by comparison, a relatively new field. Since PTPs do not require a small molecule cofactor they generally show a low propensity to bind a small molecule inhibitor. Nevertheless there are now examples of highly potent PTP inhibitors that provide promising proof-of-principle that PTPs are druggable. Most PTP inhibitors have a charged or highly polar functional group that mimics the phosphotyrosine residue, that often leads to poor ADME and cell permeability properties.
We will report our efforts to address the problems of cell permeability we have encountered in our Shp2 PTP inhibitor program. We have previously reported a series of isatin based Shp2 inhibitors based on a compound (NSC-117199) identified from screen of the NCI Diversity Set. We synthesized &gt;100 analogs of NSC-117199 in our lead optimization effort, which yielded several compounds with approximately 50-fold increase in potency and &gt; 10-fold increase in selectivity (Shp2 versus Shp1). However, these Shp2 PTP inhibitors have either a polar nitro or carboxyl group and have no detectable cellular activity. We will report three approaches to address this problem. The first approach was to prepare neutral ester prodrugs. Several compounds have clearly demonstrable activity against Shp2 in cells. A series of esters has also been designed to also improve the water solubility of the PTP inhibitor. A second approach taken was to further modify the isatin scaffold that does not necessitate the use of a prodrug strategy. We will report the discovery of new isatins related to NSC-117199 that have new modifications that result in cell active Shp2 inhibitors. Finally we will report the discovery and preliminary optimization of new classes of cell active Shp2 inhibitors based on alternative scaffolds.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 761.