Novel Small-Molecule Inhibitors of Bcl-2/Bcl-xL Protein*

描述（由申请人提供）现在已经确定，癌细胞进行凋亡的能力受损在癌细胞对化疗或放疗的抗性以及目前抗癌药物的失败中起着重要作用。因此，未来设计新的分子靶向疗法的努力必须包括新的策略

DESCRIPTION (provided by applicant) 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.