Potent and selective G protein-coupled receptor kinase 5 inhibitors: Design, synthesis, evaluation, and X-ray structural studies

We report here design of a series of highly selective, potent, non-covalent, and drug-like G protein-coupled receptor kinase 5 (GRK5) inhibitors. GRK5 is an important target for drug development for potential treatment of heart failure and cancer. Utilizing pyrroloindolinone as the main scaffold, which is embedded in the FDA-approved, orally bioavailable anti-cancer drug, sunitinib, we used structure-based design to generate a series of noncovalent, and drug-like GRK5 inhibitors. Several compounds exhibited low nanomolar potency and high selectivity against the related kinase GRK2. Three high-resolution X-ray crystal structures of GRK5-inhibitor complexes were determined to obtain insights into the ligand-binding site interactions. The current structure-activity studies and X-ray structural insights will further enable development of GRK5 inhibitor-based new treatments against cancer and heart diseases.