Generation of Highly Selective, Potent, and Covalent G Protein-Coupled Receptor Kinase 5 Inhibitors

The ability of G protein-coupled receptor (GPCR) kinases (GRKs)
to regulate the desensitization of GPCRs has made GRK2 and GRK5 attractive
targets for treating diseases such as heart failure and cancer. Previously,
our work showed that Cys474, a GRK5 subfamily-specific residue located
on a flexible loop adjacent to the active site, can be used as a covalent
handle to achieve selective inhibition of GRK5 over GRK2 subfamily
members. However, the potency of the most selective inhibitors remained
modest. Herein, we describe a successful campaign to adapt an indolinone
scaffold with covalent warheads, resulting in a series of 2-haloacetyl-containing
compounds that react quickly and exhibit three orders of magnitude
selectivity for GRK5 over GRK2 and low nanomolar potency. They however
retain a similar selectivity profile across the kinome as the core
scaffold, which was based on Sunitinib.