Generation of Highly Selective, Potent, and Covalent G Protein-Coupled Receptor Kinase 5 Inhibitors
Year: 2021
Type: article
Abstract: 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.
Source: Journal of Medicinal Chemistry
Institutions: University of Michigan, Purdue University West Lafayette
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Awards: Structure and Function of the LPLA2/LCAT Acyltransferase Family, G1468576729, G protein-coupled receptor kinase inhibitors as therapeutics for heart failure and hypertrophy, GPCR - Linked RhoGEFs in Tumor Growth and Metastasis, G4675322906, Structural basis of GPCR mediated GRK activation, Structure, function, and inhibition of G protein-coupled receptor kinases, Regulation of the metastasis promoting chemokine receptor ACKR3 by GPCR kinases, Gβγ and arrestins
OpenAlex ID: W3119986898