Activation of procaspases with small molecules

描述（由申请人提供）：本提案的主要目标是采用多学科的方法来发现和表征新的小分子，这些小分子靶向原aspase 3、7和9的变构表面空腔，以引发激动作用。理想情况下，细胞内这些“效应”半胱天冬酶的小分子激活剂将促进细胞凋亡，取代上游“启动剂”半胱天冬酶正常的、高度控制的蛋白水解激活，或合并到凋亡体中。通过高通量筛选和片段捕获来鉴定和表征这些变构位点和相应的激动剂，将进一步阐明在没有caspase 3和7蛋白水解裂解的情况下激活时发生的结构重排。此外，这些结果将揭示凋亡复合物组装过程中procaspase 9的激活机制。最终目标是确定促进肿瘤细胞凋亡的新机制和先导化合物，作为实现caspase定向化疗治疗的重要第一步。procaspase活化对细胞凋亡调控的潜在益处也将在开发用于药物发现的靶向蛋白的新方法中获得重大回报。

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.