G protein-coupled receptor kinase selective small molecule inhibitors (843.9)

Inhibition of G protein‐coupled receptor kinase 2 (GRK2) and GRK5 has emerged as potential therapeutic routes for the treatment of heart failure and cardiac hypertrophy. However, there are no commercially available small molecule therapeutics selective for either of these kinases. High‐throughput screening campaigns with representative GRKs from each subfamily (GRK1, GRK2, and GRK5) have identified first generation small molecule inhibitors with low‐micromolar potency and orders of magnitude selectivity between GRKs. The most potent of these scaffolds have additionally been shown to mediate increased contractility in isolated cardiomyocytes as well as whole animals, thus demonstrating their potential to be developed into viable therapeutics. Crystallographic analysis of several GRK‐scaffold complexes reveal molecular mechanisms of selectivity among GRKs and AGC kinases. Based on these structures, iterative rounds of rational design have resulted in compounds with nanomolar potency, high subfamily selectivity, which has provided new insights into structure activity relationships. These compounds form the basis of a novel ‘GRK inhibitor toolkit’ that can be used to elucidate GRK roles in cellular signaling and spur development of novel therapeutics. Grant Funding Source : NIH grants [HL071818 & HL086865] to J.J.G.T. and the American Heart Association [N014938] K.T.H.