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.
Public Health Relevance Statement: Kinases are proteins that are important mediators of signal transduction pathways and their activity inside cells is tightly regulated. The deregulation of kinase activity is implicated in a wide range of diseases from cancer to neurodegeneration. Importantly, kinases are excellent targets for drug development with many successes. Yet, only a small number of kinases have been targeted for drug discovery, which is primarily due to lack of information on their role in human biology and druggability. The purpose of our application is to develop state of the art chemical tools that can be used by researchers to understand the role of the vast number of understudied kinases, thereby validating them as new drug targets and thereby accelerate the development of new therapeutics for a wide range of human diseases.
Project Terms: Academia; Address; Affinity; assay development; base; Binding; Biological Assay; Biology; Cardiovascular Diseases; Cells; chemical binding; Chemicals; Cloning; Collaborations; Communities; cost; Coupled; Data; Data Set; Databases; Deposition; Development; Diabetes Mellitus; Dimerization; Disease; drug development; drug discovery; Drug resistance; Drug Targeting; Environment; Evaluation; Functional disorder; Funding Mechanisms; Generations; Goals; Grant; Human; Human Biology; human disease; Human Genome; Hybrids; Industry; Inflammation; inhibitor/antagonist; kinase inhibitor; knock-down; Knowledge; Libraries; Ligands; Luciferases; luminescence; Malignant Neoplasms; Marketing; Mediator of activation protein; member; mutant; Nerve Degeneration; new therapeutic target; next generation; novel drug class; novel therapeutics; Pathology; Pharmaceutical Chemistry; Phase; Phosphotransferases; Physiology; Play; Protein Kinase; Public Domains; Publishing; Reagent; Reporting; Research; research and development; Research Personnel; Resources; Role; screening; Services; Signal Transduction; Signal Transduction Pathway; small molecule; small molecule libraries; success; targeted treatment; Technology; Testing; Therapeutic Intervention; tool; Validation
