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

  • Eur J Med Chem. 2024 Jan 15:264:115931. doi: 10.1016/j.ejmech.2023.115931.
Yueyi Chen  1 ,  Amol Sonawane  2 ,  Rajesh Manda  2 ,  Ranjith Kumar Gadi  2 ,  John J G Tesmer  1 ,  Arun K Ghosh  3
Affiliations
  • 1. Department of Biological Sciences, Purdue University, West Lafayette, IN, 47907, USA; Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN, 47907, USA.
  • 2. Department of Chemistry, Purdue University, West Lafayette, IN, 47907, USA.
  • 3. Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN, 47907, USA; Department of Chemistry, Purdue University, West Lafayette, IN, 47907, USA. Electronic address: [email protected].
PMID: 38016297 DOI: 10.1016/j.ejmech.2023.115931
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 IC50 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.

Keywords
Covalent; GRK5 inhibitors; Reversible; Sunitinib; Synthesis; X-ray crystal structure.