Novel Compounds and a Mitochondria Target Against Cancer

新型化合物和线粒体抗癌靶点

基本信息

批准号：
7020739
负责人：
ANTHONY W OPIPARI
金额：
$ 24.29万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-03-09 至 2009-02-28
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): A combinatorial benzodiazepine library was probed for pro-apoptotic members. These experiments yielded a promising family of novel cytotoxic molecules, the lead compound of which is designated Bz-423. Bz-423 has a novel mechanism of action and target relative to known apoptotic small molecules and is active against tumor cell growth both in vitro and in vivo. Bz-423 induces a mitochondria-dependent apoptotic pathway, in which the primary signaling event is a robust increase in reactive oxygen. Experiments with isolated mitochondria and screening of a phage display cDNA library for binding partners identified the oligomycin sensitivity conferring protein (OSCP) as a target. Experiments with purified recombinant OSCP resulted in binding isotherms indicating nanomolar affinity, strongly supporting the target's validity. We propose experiments aimed at elucidating critical elements of the mechanism of action related to this target in an effort to determine the therapeutic potential of this class of agents against cancer. Experiments will validate this target at the biochemical and cellular levels. The potential of these compounds to block proliferation and the mechanism leading to this alternative response will be explored. Experiments using an animal model of tumor growth will validate the molecular target and pharmacodynamic responses in vivo and relate these to effects on tumor growth. These studies form the basis of a platform of research to identify the therapeutic use of this new class of molecules and to evaluate the possibility that the OSCP is a tractable drug target for cancer.

描述（由申请人提供）：对组合苯二氮卓库进行了促凋亡成员的探索。这些实验产生了一个有前途的新型细胞毒性分子家族，其先导化合物被命名为 Bz-423。相对于已知的凋亡小分子，Bz-423 具有新颖的作用机制和靶点，并且在体外和体内均具有抗肿瘤细胞生长的活性。 Bz-423 诱导线粒体依赖性细胞凋亡途径，其中主要信号传导事件是活性氧的强劲增加。使用分离的线粒体进行实验并筛选噬菌体展示 cDNA 文库以寻找结合伴侣，确定了寡霉素敏感性赋予蛋白 (OSCP) 作为靶标。使用纯化的重组 OSCP 进行的实验产生了表明纳摩尔亲和力的结合等温线，有力地支持了目标的有效性。我们提出了旨在阐明与该靶点相关的作用机制的关键要素的实验，以确定此类药物抗癌的治疗潜力。实验将在生化和细胞水平上验证该目标。将探索这些化合物阻止增殖的潜力以及导致这种替代反应的机制。使用肿瘤生长动物模型进行的实验将验证体内分子靶点和药效学反应，并将其与对肿瘤生长的影响联系起来。这些研究构成了一个研究平台的基础，该平台旨在确定此类新型分子的治疗用途，并评估 OSCP 作为癌症易治疗药物靶点的可能性。