It is now firmly established that the impaired ability of cancer cells to undergo apoptosis plays a major role in the resistance of cancer cells to chemotherapy or radiation and for the failure of current anti-cancer drugs. Hence, future efforts toward designing new molecular-targeted therapies must include novel strategies that specifically target the resistance of cancer cells to apoptosis. Bcl-2 and Bcl-xL proteins represent exciting anti-apoptotic molecular targets for designing new anti-cancer drugs by aiming at overcoming resistance of cancer cells to apoptosis. This NCDDG application proposes to design and develop novel nonpeptidic, small-molecule inhibitors of Bcl-2 and Bcl-xL proteins as a new class of anti-cancer drugs through a contemporary, multidisciplinary and integrated drug discovery approach. Our overall hypothesis is that smallmolecule inhibitors of Bcl-2 and Bcl-xL will overcome apoptosis-resistance of cancer cells with high levels of Bcl-2/Bcl-xL overexpression. Such small-molecule inhibitors will also have a high selectivity since most normal cells have low levels of Bcl-2/Bcl-xL proteins and do not depend upon Bcl-2/Bcl-xL for survival. This application consists of three inter-dependent and integrated research Programs: 1. Computational structure-based design, chemical synthesis, biochemical characterization and molecular mechanism of action studies (Shaomeng Wang, Ph.D. University of Michigan) 2. Determination of high-resolution experimental three-dimensional structures of small-molecule inhibitors in complex with Bcl-2 and Bcl-xL by X-ray crystallography and by nuclear magnetic resonance (NMR) methods; (Jeanne Stuckey, Ph.D. University of Michigan and YorkTomita, Ph.D. Georgetown University) 3. The therapeutic potential, pharmacology, and toxicity of promising small-molecule inhibitors in preclinical models of human hormone-refractory prostate cancer. (Kenneth Pienta, M.D. University of Michigan) The overall goal of this NCDDG drug discovery program is to bring a highly potent and promising smallmolecule inhibitor of Bcl-2 and Bcl-xL proteins for advanced preclinical development in anticipation of an IND filing with a commercial partner. It is predicted that a potent small-molecule inhibitor will not only be useful for the treatment of hormone refractory prostate cancer but also for many other types of human cancer, in which Bcl-2 and/or Bcl-xL is highly overexpressed and for which traditional therapy has failed.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program--Cooperative Agreements (U19)
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Application #
Study Section
Special Emphasis Panel (ZCA1-SRRB-U (J1))
Program Officer
Song, Min-Kyung H
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University of Michigan Ann Arbor
Internal Medicine/Medicine
Schools of Medicine
Ann Arbor
United States
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Bai, Longchuan; Chen, Jianfang; McEachern, Donna et al. (2014) BM-1197: a novel and specific Bcl-2/Bcl-xL inhibitor inducing complete and long-lasting tumor regression in vivo. PLoS One 9:e99404
Aguilar, Angelo; Zhou, Haibin; Chen, Jianfang et al. (2013) A potent and highly efficacious Bcl-2/Bcl-xL inhibitor. J Med Chem 56:3048-3067
Chen, Jianfang; Zhou, Haibin; Aguilar, Angelo et al. (2012) Structure-based discovery of BM-957 as a potent small-molecule inhibitor of Bcl-2 and Bcl-xL capable of achieving complete tumor regression. J Med Chem 55:8502-14
Zhou, Haibin; Aguilar, Angelo; Chen, Jianfang et al. (2012) Structure-based design of potent Bcl-2/Bcl-xL inhibitors with strong in vivo antitumor activity. J Med Chem 55:6149-61
Imai, Atsushi; Zeitlin, Benjamin D; Visioli, Fernanda et al. (2012) Metronomic dosing of BH3 mimetic small molecule yields robust antiangiogenic and antitumor effects. Cancer Res 72:716-25
Zhou, Haibin; Chen, Jianfang; Meagher, Jennifer L et al. (2012) Correction to Design of Bcl-2 and Bcl-xL Inhibitors with Subnanomolar Binding Affinities Based upon a New Scaffold. J Med Chem 55:5987
Zhou, Haibin; Chen, Jianfang; Meagher, Jennifer L et al. (2012) Design of Bcl-2 and Bcl-xL inhibitors with subnanomolar binding affinities based upon a new scaffold. J Med Chem 55:4664-82
Azmi, Asfar S; Aboukameel, Amro; Banerjee, Sanjeev et al. (2010) MDM2 inhibitor MI-319 in combination with cisplatin is an effective treatment for pancreatic cancer independent of p53 function. Eur J Cancer 46:1122-31
Azmi, Asfar S; Philip, Philip A; Aboukameel, A et al. (2010) Reactivation of p53 by novel MDM2 inhibitors: implications for pancreatic cancer therapy. Curr Cancer Drug Targets 10:319-31
McGregor, Natalie; Patel, Lalit; Craig, Matthew et al. (2010) AT-101 (R-(-)-gossypol acetic acid) enhances the effectiveness of androgen deprivation therapy in the VCaP prostate cancer model. J Cell Biochem 110:1187-94

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