Tools for Accelerating R&D for Historically Understudied Protein Kinases

蛋白激酶在人类生理的几乎每一个方面都是核心角色，并作为 信号转导的关键介体。许多激酶的功能障碍与 癌症、糖尿病、炎症和心血管疾病，其中许多都是有效的治疗目标 治疗性干预。人类基因组编码约518个蛋白激酶。然而，这25人左右 上市的蛋白激酶药物，只针对人类基因组的一小部分。一个更伟大的 部分仍未被探索，关于它们在细胞信号转导中的作用的信息很少。 化学工具可以在目标发现和验证中发挥关键作用。有选择性的和强有力的 小分子激酶抑制剂可以用来通过药理学来解决这一知识缺口 在其天然环境中敲除一种靶蛋白激酶并探讨其作用 对细胞信号和疾病病理学的抑制。 我们的目标是系统地关注大量历史上研究不足的激酶， 由于缺乏对机制和功能的了解，目前无法下药 由于缺乏试剂和相关的分析方法来衡量选择性，这一差距将得到解决。 通过高质量的化学探头开发，能够选择性的讯问功能 靶向激活酶。在第二阶段期间，我们将反复a)开发低成本、可靠的分析方法 使用我们的平台分裂荧光素酶技术来研究未被充分研究的激酶，以及，b)开发高 高质量的化学探针，可以帮助去卷曲的激酶生物学和靶标发现。这个 根据这项拨款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.