Activation of procaspases with small molecules

用小分子激活天冬氨酸蛋白酶原

• 批准号: 7465499
• 负责人: Dennis William Wolan
• 金额: $ 5.2万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-28 至 2009-07-27
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7465499
• 关键词: Adopted; Agonist; Allosteric Site; Apoptosis; Apoptotic; Area; Binding; Biological Assay; Caspase; Cell Death; Chemistry; Classification; Complex; Computing Methodologies; Crystallography; DNA Sequence Rearrangement; Development; Family member; Fellowship; Goals; In Vitro; Individual; Lead; Libraries; Light; Mass Spectrum Analysis; Methods; Molecular Conformation; Mutagenesis; Names; Pathway interactions; Property; Proteins; Proteolysis; Regulation; Rewards; Roentgen Rays; Site; Structure; Suggestion; Sulfhydryl Compounds; Surface; System; Up-Regulation; Work; apoptotic protease-activating factor 1; base; caspase-3; caspase-8; caspase-9; chemotherapeutic agent; combinatorial; comparative; cytochrome c; design; dimer; drug discovery; high throughput screening; in vivo; interest; neoplastic cell; novel; pro-caspase-9; small molecule

DESCRIPTION (provided by applicant): The primary goal of this proposal is to adopt a multi-disciplinary approach towards the discovery and characterization of novel small molecules that target allosteric surface cavities of procaspases 3, 7 and 9 in order to elicit agonistic activity. Ideally, intracellular small molecule activators of these "effector" procaspases will then promote cellular apoptosis in lieu of the normal, highly-controlled proteolytic activation by upstream "initiator" caspases, or incorporation into the apoptosome. Identification and characterization of these allosteric sites and corresponding agonists with high throughput screening and fragment-trapping will further elucidate the structural rearrangements that occur upon activation in the absence of proteolytic cleavage of caspases 3 and 7. Furthermore, these results will shed light on the activation mechanism of procaspase 9 during assembly of the apoptosome complex. The ultimate goal is to identify novel mechanisms and lead compounds that promote apoptosis in tumor cells as a major first step towards caspase-directed chemotherapeutic therapies. The potential benefits to apoptosis regulation by procaspase activation will also have significant rewards in the development of novel methods to target proteins for drug discovery.

描述（由申请人提供）：该提案的主要目标是采用多学科的方法来发现和表征新型的小分子，以靶向Procaspase 3、7和9的靶向变构表面腔，以引起激动活性。理想情况下，这些“效应子” procass酶的细胞内小分子活化剂将促进细胞凋亡，以代替上游“引发剂” caspases或掺入凋亡组的正常，高度控制的蛋白水解活化。这些变构位点以及具有高吞吐量筛选和碎片捕获的相应激动剂的识别和表征将进一步阐明在没有蛋白水解切割3和7的情况下激活后发生的结构重排。此外，这些结果将使Procaspase 9的激活机制在Apopoptosose组成过程中的激活机制降低。最终目标是确定新的机制和铅化合物，这些化合物促进肿瘤细胞的凋亡，这是迈向caspase指导化学治疗疗法的主要第一步。 propaspase激活对细胞凋亡调节的潜在益处也将在靶向蛋白质发现药物发现的新方法的发展方面具有重大回报。

项目成果

Small-molecule activators of a proenzyme.

• DOI: 10.1126/science.1177585
• 发表时间: 2009-11-06
• 期刊: Science (New York, N.Y.)
• 作者: Wolan DW;Zorn JA;Gray DC;Wells JA
• 通讯作者: Wells JA