Tools for Accelerating R&D for Historically Understudied Protein Kinases

Protein kinases are central players in almost every aspect of human physiology and serve as critical mediators of signal transductionThe dysfunction of many kinases is implicated in cancerdiabetesinflammationand cardiovascular diseases and many are validated targets for therapeutic interventionThe human genome encodesprotein kinasesYettheor so marketed protein kinase drugstarget only a small fraction of the human kinomeA greater portion remains unexploredwith very little information available on their role in cell signalingChemical tools can play a pivotal role in target discovery and validationSelective 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 pathologyOur goal is to systematically focus on the vast number of historically understudied kinaseswhich are currently non druggable due to lack of mechanistic and functional understanding due to a paucity of reagents and associated assays to gauge selectivityThis gap will be addressed by high quality chemical probe developmentcapable of selectively interrogating function of target kinasesDuring the Phase II periodwe will iteratively adevelop low costrobust assays using our platform split luciferase technology for the understudied kinases andbdevelop highquality chemical probeswhich can help deconvolute kinase biology and target discoveryThe chemical probe sets developed under this grant will be available as a resource to the research community