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

描述（由申请人提供） 现在已经确定，癌细胞经历凋亡的能力受损在癌细胞对化疗或放射的抗性以及当前抗癌药物的失败中起主要作用。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， 特异性靶向癌细胞对凋亡的抗性。Bcl-2和Bcl-xL蛋白代表了令人兴奋的抗凋亡分子靶标，用于通过旨在克服癌细胞对凋亡的抗性来设计新的抗癌药物。该NCDDG申请提出通过当代，多学科和综合药物发现方法设计和开发新型Bcl-2和Bcl-xL蛋白的非肽类小分子抑制剂作为一类新的抗癌药物。我们的总体假设是Bcl-2和Bcl-xL的小分子抑制剂将克服具有高水平Bcl-2/Bcl-xL过表达的癌细胞的凋亡抗性。这种小分子抑制剂也将具有高选择性，因为大多数抑制剂都具有高选择性。 正常细胞具有低水平的Bcl-2/Bcl-xL蛋白，并且不依赖Bcl-2/Bcl-xL存活。该应用程序包括三个相互依赖和综合的研究计划： 1.基于计算结构的设计、化学合成、生化表征和分子作用机制研究（Shaomeng Wang，Ph.D.密歇根大学（University of Michigan） 2.通过X射线晶体学和核磁共振（NMR）方法测定与Bcl-2和Bcl-xL复合的小分子抑制剂的高分辨率实验三维结构;（Jeanne Stuckey，Ph.D.密歇根大学和约克大学富田博士乔治城大学（Georgetown University）有前景的小分子抑制剂在人类难治性前列腺癌临床前模型中的治疗潜力、药理学和毒性。（Kenneth Pienta，医学博士）该NCDDG药物发现计划的总体目标是为先进的临床前开发带来一种高效且有前途的Bcl-2和Bcl-xL蛋白小分子抑制剂，以期待与商业合作伙伴的IND申请。据预测，有效的小分子抑制剂将不仅可用于治疗激素难治性前列腺癌，而且可用于许多其他类型的人类癌症，其中Bcl-2和/或Bcl-xL高度过表达，并且传统疗法已失败。

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.