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

说明书(申请人提供)现已确定，癌细胞进行凋亡的能力受损在癌细胞对化疗或辐射的抵抗以及当前抗癌药物的失败中起着主要作用。因此，未来设计新的分子靶向疗法的努力必须包括新的战略， 特别针对癌细胞对凋亡的抵抗力。BCL-2和BCL-XL蛋白代表着激动人心的抗凋亡分子靶点，旨在通过克服癌细胞对凋亡的抵抗来设计新的抗癌药物。这项NCDDG申请建议通过当代、多学科和集成的药物发现方法，设计和开发新型的非肽类、小分子的Bcl2和Bclxl蛋白抑制剂，作为一类新的抗癌药物。我们的总体假设是，小分子的Bcl2和Bclxl抑制剂将克服高水平Bcl2/Bclxl过表达的癌细胞的凋亡抵抗。这种小分子抑制剂也将具有高选择性，因为大多数 正常细胞低水平表达Bcl2/Bclxl蛋白，不依赖于Bcl2/Bclxl生存。本申请由三个相互依赖和综合的研究计划组成： 1.基于计算结构的设计、化学合成、生化表征和作用的分子机制研究(密歇根大学博士王少蒙) 2.用X射线结晶学和核磁共振方法测定小分子抑制剂与Bc l-2和Bc l-xl形成的复合体的高分辨率实验三维结构；(Jeanne Stuckey，博士，密歇根大学和York Tomita，博士，乔治敦大学)3.在人类激素难治性前列腺癌的临床前模型中，有希望的小分子抑制剂的治疗潜力、药理学和毒性。(密歇根大学医学博士肯尼斯·皮恩塔)这一NCDDG药物发现计划的总体目标是带来一种高度有效且前景看好的Bcl-2和Bcl-XL蛋白小分子抑制剂，用于先进的临床前开发，预计将向商业合作伙伴提交IND文件。据预测，一种有效的小分子抑制物不仅可用于激素难治性前列腺癌的治疗，还可用于许多其他类型的人类癌症，在这些癌症中，Bcl2和/或Bclxl高度过度表达，传统治疗已失败。

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.