Development of a New Class of Potent and Highly Selective G Protein-coupled Receptor Kinase 5 Inhibitors and Structural Insight from Crystal Structures of Inhibitor Complexes

Overview

Journal Eur J Med Chem

Specialty Chemistry

Date 2023 Nov 28

PMID 38016297

Authors

Yueyi Chen

Amol Sonawane

Rajesh Manda

Ranjith Kumar Gadi

John J G Tesmer

Arun K Ghosh

Affiliations

Soon will be listed here.

Abstract

G protein-coupled receptor kinase 5 (GRK5) is an important drug development target for heart failure, cardiac hypertrophy, and cancer. We have designed and developed a new class of highly selective, potent, and non-covalent GRK5 inhibitors. One of the inhibitors displayed GRK5 IC value of 10 nM and exhibited >100,000-fold selectivity over GRK2. The X-ray structure of a ketoamide-derived inhibitor-bound GRK5 showed the formation of a hemithioketal intermediate with active site Cys474 in the GRK5 active site and provided new insights into the ligand-binding site interactions responsible for high selectivity. The current studies serve as an important guide to therapeutic GRK5 inhibitor drug development.

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