Tools for Accelerating R&D for Historically Understudied Protein Kinases

蛋白激酶在人类生理学的几乎每个方面都是中心角色， 信号转导的关键介质。许多激酶的功能障碍与 癌症、糖尿病、炎症和心血管疾病，许多都是经验证的靶点， 治疗干预人类基因组编码约518种蛋白激酶。然而，25个左右的 市售的蛋白激酶药物仅靶向人激酶组的一小部分。更大 部分仍然未被探索，关于它们在细胞信号传导中的作用的信息非常少。 化学工具可以在目标发现和验证中发挥关键作用。选择性和有效 小分子激酶抑制剂可用于通过药理学方法解决这一知识缺口， 在其天然环境中敲低靶蛋白激酶，并探测 抑制细胞信号传导和疾病病理学。 我们的目标是系统地关注大量历史上研究不足的激酶， 由于缺乏对机械和功能的理解， 缺乏试剂和相关的测定来衡量选择性，这一差距将得到解决 通过高质量的化学探针开发，能够选择性地询问功能， 靶激酶。在第二阶段期间，我们将反复a）开发低成本、稳健的检测方法 使用我们的平台分裂荧光素酶技术用于未充分研究的激酶，和，B）开发高- 高质量的化学探针，可以帮助解卷积激酶生物学和目标发现。的 在此资助下开发的化学探针组将作为研究的资源 社区

Protein kinases are central players in almost every aspect of human physiology and serve as critical mediators of signal transduction. The dysfunction of many kinases is implicated in cancer, diabetes, inflammation, and cardiovascular diseases and many are validated targets for therapeutic intervention. The human genome encodes ~518 protein kinases. Yet, the 25 or so marketed protein kinase drugs, target only a small fraction of the human kinome. A greater portion remains unexplored, with very little information available on their role in cell signaling. Chemical tools can play a pivotal role in target discovery and validation. Selective and potent small-molecule kinase inhibitors can be used to address this knowledge gap by pharmacological knockdown of a target protein-kinase in their native environment and probe the effect of inhibition on cell signaling and disease pathology. Our goal is to systematically focus on the vast number of historically understudied kinases, which are currently non-druggable due to lack of mechanistic and functional understanding due to a paucity of reagents and associated assays to gauge selectivity, This gap will be addressed by high-quality chemical probe development, capable of selectively interrogating function of target kinases. During the Phase II period, we will iteratively a) develop low-cost, robust assays using our platform split-luciferase technology for the understudied kinases and, b) develop high- quality chemical probes, which can help deconvolute kinase biology and target discovery. The chemical probe sets developed under this grant will be available as a resource to the research community.