High Throughput Screening Technology for Allosteric Kinase Inhibitors

DESCRIPTION (provided by applicant): Protein kinases play a central role in many signaling pathways and are key effectors of cellular functions. Abnormalities in protein kinase activity, either due to changes in enzyme levels or mutations in the kinase str ucture, are responsible for pathologies. As such, protein kinases inhibitors can potentially be developed as therapeutics for many diseases, including cancer, central nervous system disorders and inflammation. Drug discovery efforts have primarily identifi ed small molecule ligands that compete directly with ATP binding. However, molecules that inhibit one kinase by binding at the highly conserved ATP site often inhibit other kinases, resulting in potential drug safety issues. Approaches to target drugs to t he inactive conformation may provide the means to identify selective inhibitors. The problem is that there are not many ways to detect the inactive conformation of protein kinases and none that can be easily employed for drug discovery. Encode Bio has deve loped an optical technology which can be employed to identify allosteric regulators of protein kinases that stabilize the inactive conformation of protein kinases. We propose to make the next critical technological jump in developing the approach for drug discovery by generating a system to mass produce the requisite assa reagents in quantities needed for high throughput screening of large chemical libraries. PUBLIC HEALTH RELEVANCE: Protein kinases play important roles in regulating most cellular functions . We will develop novel high throughput assays with universal utility to identify protein kinase inhibitors that bind outside the ATP-binding site. These assays could be used to accelerate the development of therapeutics for many diseases, including cancer , central nervous system disorders and inflammation. We will accelerate development of allosteric kinase inhibitors with potentially better selectivity and safety profiles.