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：
7189835
负责人：
ANTHONY W OPIPARI
金额：
$ 23.79万
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

来源：
https://reporter.nih.gov/project-details/7189835
关键词：
ATP Synthesis Pathway Address Affinity Animal Model Animals Apoptotic Benzodiazepines Binding Biochemical Biological Assay Bz-423 Cell Line Cells Class Cultured Cells Cultured Tumor Cells DNA Microarray Chip DNA Microarray format Data Drug Delivery Systems Elements Event Family Gene Expression Growth Hydrolysis In Vitro Lead Libraries Malignant Neoplasms Mammalian Cell Mediating Microarray Analysis Mitochondria Modeling Molecular Target Oxygen Pathway interactions Phage Display Pharmacodynamics Polyamines Process Protein Binding Recombinants Relative (related person)Research Respiration Screening procedure Series Signal Transduction Structure Testing Therapeutic Therapeutic Uses analog base cDNA Library cancer cell cell growth combinatorial comparative cytotoxic cytotoxicity in vivo killings member neoplastic cell novel oligomycin sensitivity-conferring protein pre-clinical protein expression research clinical testing research study response small molecule tumor tumor growth

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）：对培养基构件探测了组合苯二氮卓图库。这些实验产生了一个有前途的新细胞毒性分子家族，其铅化合物被指定为BZ-423。 BZ-423具有相对于已知凋亡小分子的新型作用机理和靶标的机理，并且在体外和体内都对肿瘤细胞生长具有活性。 BZ-423诱导线粒体依赖性凋亡途径，其中主要信号事件是活性氧的强大增加。用分离的线粒体和噬菌体显示cDNA文库筛选的实验，以确定寡霉素敏感性赋予蛋白质（OSCP）为靶标。纯化的重组OSCP的实验导致结合等温线表明纳摩尔亲和力，强烈支持目标的有效性。我们提出了旨在阐明与该目标相关的作用机理的关键要素的实验，以确定这种类药物对癌症的治疗潜力。实验将在生化和细胞水平上验证该靶标。这些化合物阻断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的实验将验证体内的分子靶标和药效反应，并将其与对肿瘤生长的影响相关。这些研究构成了研究平台的基础，以鉴定这种新的分子的治疗用途，并评估OSCP是癌症的可探讨药物靶标的可能性。