New Molecular Probes For Protein Kinases

摘要：蛋白激酶活性的失调与许多 疾病，包括癌症、糖尿病和慢性炎症。因此，蛋白质 在现代药物中，激酶已成为最重要的药物靶点之一 发现号。这些努力已导致开发了大量的小型 与蛋白激酶的ATP结合位点相互作用的分子抑制剂 能够阻断它们的催化活性。有趣的是，许多这样的药理作用 试剂通过以下方式利用蛋白激酶的ATP结合位点的构象灵活性 结合到不同的活性部位构象。ATP--稳定的竞争性抑制物 多结构域蛋白激酶的不同ATP结合位点构象 显示出不同程度地影响活性部位以外的结构域和相互作用。这 提案将探索如何稳定Src家族的不同活性位点构象 激酶影响其亚细胞定位、分子间相互作用和信号传递。 行为。一套化学遗传和化学蛋白质组学工具被提出用于 探索构象选择性、Src家族蛋白激酶抑制的后果 不同的蜂窝环境。

Abstract: Dysregulation of protein kinase activity has been implicated in a number of diseases, including cancer, diabetes, and chronic inflammation. Therefore, protein kinases have emerged as one of the most important drug targets in modern drug discovery. These efforts have resulted in the development of a vast array of small molecule inhibitors that interact with the ATP-binding sites of protein kinases and are able to block their catalytic activities. Interestingly, many of these pharmacological agents exploit the conformational flexibility of the ATP-binding sites of protein kinases by binding to different active site conformations. ATP-competitive inhibitors that stabilize different ATP-binding site conformations of multi-domain protein kinases have been shown to divergently affect domains and interactions outside of their active sites. This proposal will explore how stabilizing different active site conformations of Src-Family Kinases affect their sub-cellular localization, inter-molecular interactions, and signaling behavior. A suite of chemical genetic and chemical proteomic tools is proposed to explore the consequences of conformation-selective, Src-Family Kinase inhibition in diverse cellular contexts.