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靶向前半胱氨酸蛋白酶3、7和9的变构表面空腔以引发激动活性的新型小分子。理想地，这些“效应物”半胱天冬酶原的细胞内小分子活化剂然后将促进细胞凋亡，代替通过上游“起始物”半胱天冬酶的正常的、高度受控的蛋白水解活化，或掺入到细胞凋亡体中。通过高通量筛选和片段捕获对这些变构位点和相应激动剂进行鉴定和表征，将进一步阐明在不存在半胱天冬酶3和7的蛋白水解切割的情况下活化后发生的结构重排。此外，这些结果将揭示在装配的复合体的半胱氨酸天冬氨酸蛋白酶原9的激活机制。最终的目标是确定新的机制和领导化合物，促进肿瘤细胞凋亡作为一个主要的第一步半胱天冬酶导向化疗。通过半胱天冬酶原激活对细胞凋亡调节的潜在益处也将在开发用于药物发现的靶向蛋白质的新方法中具有显著的回报。

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.