权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Mcl-1/Bfl-1 in apoptosis and signal transduction: a structure/function approach

Mcl-1/Bfl-1 在细胞凋亡和信号转导中的作用：结构/功能方法

基本信息

批准号：
10520035
负责人：
Maurizio Pellecchia
金额：
$ 42.46万
依托单位：
UNIVERSITY OF CALIFORNIA RIVERSIDE
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-09 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10520035
关键词：
Affinity Apoptosis Apoptotic BAX gene BCL-2 Protein BCL2 gene BCL2L1 gene BCL2L11 gene BH3 Domain BH3 peptide Binding Cancer cell line Cell Death Cell Death Inhibition Cell Line Cell Membrane Permeability Cell Survival Cells Chronic Lymphocytic Leukemia Development Disulfides Family Goals Human Immunotherapy Induction of Apoptosis Laboratories Lead Leukemic Cell Lymphoma cell MCL1 gene Mediating Methods Mus Oncogenes Outer Mitochondrial Membrane PMAIP1 gene Peptides Pharmacology Study Primary Neoplasm Protein Family Proteins Radiation Reporting Research Resistance Role Route Sampling Scheme Sentinel Signal Transduction Specificity Structure Structure-Activity Relationship Surface Therapeutic Tumor Cell Line Visit antagonist anti-cancer therapeutic anticancer activity cancer cell cancer therapy cell injury chemotherapy clinically relevant cytochrome c design drug discovery in vivo inhibitor innovation leukemia melanoma member mitochondrial membrane neoplastic cell novel overexpression pharmacologic preference prevent protein expression protein protein interaction small molecule targeted agent therapeutic target tool

项目摘要

PROJECT SUMMARY Given the pivotal role of anti-apoptotic Bcl-2 family of proteins in cancer cell survival and resistance to chemotherapy, the development of novel anti-cancer therapeutics targeting the BH3 binding groove of anti- apoptotic Bcl-2 proteins have emerged as a promising, yet challenging therapeutic goal. The recent approval of Venetoclax (ABT199), a selective Bcl-2 antagonist whose design and development spanned well over fifteen years of iterative optimizations using extensive structure-based refinements, suggested that it is indeed possible, albeit extremely challenging, to attain inhibitors of protein-protein interactions (PPIs) that are clinically relevant. However, we and others found that overexpression of both Mcl-1 and, perhaps more relevant, Bfl-1 (two other members of the Bcl-2 family protein that are not targeted by Venetoclax), confer resistance to chemotherapy and to Bcl-2 antagonists. Recent efforts from our laboratory identified possible novel routes to design potent and selective inhibitors of PPIs targeting these oncogenes that encompass structure-based design of covalent inhibitors. Hence, we propose to further investigate these innovative structure-guided drug discovery strategies and to apply them to the design of potent dual Mcl-1/Bfl-1 antagonists. If successful, our studies could result in general methods to target PPIs and could also identify innovative lead compounds for the treatment of cancer.

项目摘要考虑到抗凋亡Bcl-2蛋白家族在癌细胞存活和抗肿瘤中的关键作用，化疗，开发新的抗癌治疗靶向的BH 3结合沟的抗肿瘤药物，凋亡Bcl-2蛋白已成为一个有前途的，但具有挑战性的治疗目标。最近核准维奈托克（ABT 199），一种选择性Bcl-2拮抗剂，其设计和开发跨越了15年以上多年的迭代优化使用广泛的基于结构的改进，表明这确实是可能的，尽管非常具有挑战性，但要获得临床上有效的蛋白质-蛋白质相互作用（PPI）抑制剂，相关的然而，我们和其他人发现Mcl-1和可能更相关的Bfl-1的过度表达， (two非维奈托克靶向的Bcl-2家族蛋白的其他成员），赋予对化疗和Bcl-2拮抗剂。我们实验室最近的努力确定了可能的新途径，设计针对这些癌基因的有效和选择性PPI抑制剂，包括基于结构的设计共价抑制剂。因此，我们建议进一步研究这些创新的结构导向药物发现策略，并将其应用于有效的双重Mcl-1/Bfl-1拮抗剂的设计。如果成功，我们的研究可以产生靶向PPI的通用方法，还可以确定用于治疗癌