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方法来发现和表征以原天冬氨酸酶3、7和9的变构表面空腔为靶点的新型小分子，以诱导激动剂活性。理想情况下，这些“效应型”原天冬氨酸氨基转移酶的细胞内小分子激活剂将促进细胞凋亡，而不是由上游的“起始型”半胱氨酸酶或整合到凋亡体中的正常的、高度受控的蛋白水解性激活。通过高通量筛选和片段捕获来鉴定这些变构位点和相应的激动剂，将进一步阐明在没有caspase3和7蛋白水解性切割的情况下激活时发生的结构重排。此外，这些结果将有助于揭示原天冬氨酸酶9在端粒复合体组装过程中的激活机制。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，作为迈向caspase指导的化疗治疗的重要第一步。通过激活原天冬氨酸酶调节细胞凋亡的潜在好处也将在药物发现的靶向蛋白质的新方法的开发中获得显著的回报。

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.