Tools for Accelerating R&D for Historically Understudied Protein Kinases

加速 R 的工具

• 批准号: 9264156
• 负责人: REENA ZUTSHI
• 金额: $ 70.86万
• 依托单位: LUCEOME BIOTECHNOLOGIES, LLC
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-01 至 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9264156
• 关键词: Academia; Address; Affinity; Binding; Biological Assay; Biology; Cardiovascular Diseases; Cells; Chemicals; Cloning; Collaborations; Communities; Coupled; Data; Databases; Deposition; Development; Diabetes Mellitus; Dimerization; Disease; Drug Targeting; Drug resistance; Environment; Evaluation; Functional disorder; Funding Mechanisms; Generations; Goals; Grant; Human; Human Biology; Human Genome; Hybrids; Industry; Inflammation; Knowledge; Libraries; Ligands; Luciferases; Malignant Neoplasms; Mediator of activation protein; Nerve Degeneration; Pathology; Pharmaceutical Chemistry; Pharmacology; Phase; Phosphotransferases; Physiology; Play; Protein Kinase; Public Domains; Publishing; Reagent; Reporting; Research; Research Personnel; Resources; Role; Services; Signal Transduction; Signal Transduction Pathway; Technology; Testing; Therapeutic Intervention; Validation; assay development; base; cost; dimer; drug development; drug discovery; human disease; inhibitor/antagonist; kinase inhibitor; knock-down; luminescence; member; mutant; new therapeutic target; next generation; novel drug class; novel therapeutics; research and development; screening; small molecule; small molecule libraries; success; targeted treatment; tool

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.

蛋白激酶在人类生理学的几乎每个方面都发挥着核心作用，并作为 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，其中许多都是经过验证的目标 治疗干预。人类基因组编码约 518 种蛋白激酶。然而，25 左右 市售的蛋白激酶药物仅针对人类激酶组的一小部分。一个更大的 其中一部分尚未被探索，关于它们在细胞信号传导中的作用的信息很少。 化学工具可以在靶标发现和验证中发挥关键作用。有选择性且有效 小分子激酶抑制剂可通过药理学方法来弥补这一知识差距 在其天然环境中敲低目标蛋白激酶并探究其效果 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未被充分研究的激酶， 由于缺乏机制和功能了解，目前不可成药 由于缺乏试剂和相关测定来衡量选择性，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 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来研究待研究的激酶，b) 开发高 高质量的化学探针，有助于解开激酶生物学和靶标发现的谜题。这 根据这笔赠款开发的化学探针组将作为研究资源提供 社区。