Design, synthesis, and X-ray structural studies of a series of highly potent, selective, and drug-like G protein-coupled receptor kinase 5 inhibitors

  • Eur J Med Chem. 2025 Jan 15:282:117024. doi: 10.1016/j.ejmech.2024.117024.
Arun K Ghosh  1 ,  Yueyi Chen  2 ,  Ranjith Kumar Gadi  3 ,  Amol Sonawane  3 ,  Sandali Piladuwa Gamage  2 ,  JohnJ G Tesmer  2
Affiliations
  • 1. Department of Chemistry, Purdue University, West Lafayette, IN 47907, USA; Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN 47907, USA. Electronic address: [email protected].
  • 2. Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN 47907, USA; Department of Biological Sciences, Purdue University, West Lafayette, IN 47907, USA.
  • 3. Department of Chemistry, Purdue University, West Lafayette, IN 47907, USA.
PMID: 39549325 DOI: 10.1016/j.ejmech.2024.117024
Abstract

G protein-coupled receptor kinase 5 (GRK5) has emerged as a potential drug development target against heart failure and Cancer. A close homolog, GRK6 represents a therapeutic target for multiple myeloma. We have rationally designed a series of highly selective, potent, noncovalent, and drug-like GRK5 inhibitors. Several inhibitors exhibited low nanomolar GRK5 inhibition and high selectivity over GRK2, and, surprisingly, some were selective for GRK6. We determined high-resolution X-ray crystal structures of several inhibitors in complex with GRK5, which provide molecular insights into the ligand-binding site interactions responsible for GRK5 selectivity and potency.

Keywords
GRK2; GRK5 inhibitors; GRK6 inhibitors; Heterocyclic; Non-covalent; Sunitinib; Synthesis; X-ray crystal structure.
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