Potent, Selective, and Drug‐like G Protein‐coupled Receptor Kinase 5 and 6 Inhibitors: Design, Synthesis, and X‐ray Structural Studies

We report here the design, synthesis, and evaluation of small molecules, drug-like G protein-coupled receptor kinase 5 (GRK5) inhibitors.  GRK5 has become an important drug development target against heart failure and cancer. GRK6, a close homolog of GRK5, is considered as a possible therapeutic target for multiple myeloma. We designed a series of drug-like GRK5 inhibitors that form noncovalent interactions in the GRK5 active site.  In the design of these molecules, we utilized pyrroloindoline basic scaffold of sunitinib, an FDA approved drug and incorporated various N-heterocyclic carboxamides in the active site. Several inhibitors exhibited low nanomolar GRK5 inhibitory activity and high selectivity over GRK2.  Several compounds also displayed very potent activity and selectivity for GRK6. We determined a high-resolution X-ray crystal structure of one of these small molecule inhibitors in complex with GRK5. The structure provided important molecular insights regarding ligand-binding site interactions, GRK5 inhibition, and selectivity against GRK2.