Open AccessGeneration of Highly Selective, Potent, and Covalent G Protein-Coupled Receptor Kinase 5 Inhibitors
Author(s) -
Rachel A. Rowlands,
Qiuyan Chen,
Renee Bouley,
Larisa Avramova,
John J.G. Tesmer,
Andrew D. White
Publication year - 2021
Publication title -
journal of medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.01
H-Index - 261
eISSN - 1520-4804
pISSN - 0022-2623
DOI - 10.1021/acs.jmedchem.0c01522
Subject(s) - kinome , g protein coupled receptor kinase , chemistry , g protein coupled receptor , beta adrenergic receptor kinase , kinase , biochemistry , serine , pharmacophore , covalent bond , subfamily , receptor , pharmacology , stereochemistry , phosphorylation , biology , organic chemistry , gene
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.