2. Academic Validation
  3. Generation of Highly Selective, Potent, and Covalent G Protein-Coupled Receptor Kinase 5 Inhibitors

Generation of Highly Selective, Potent, and Covalent G Protein-Coupled Receptor Kinase 5 Inhibitors

  • J Med Chem. 2021 Jan 14;64(1):566-585. doi: 10.1021/acs.jmedchem.0c01522.
Rachel A Rowlands 1,  Qiuyan Chen 2,  Renee A Bouley 3,  Larisa V Avramova 2,  John J G Tesmer 2,  Andrew D White 1
Affiliations

Affiliations

  • 1 Vahlteich Medicinal Chemistry Core, College of Pharmacy, University of Michigan, 428 Church St, Ann Arbor, Michigan 48109, United States.
  • 2 Departments of Biological Sciences and of Medicinal Chemistry and Molecular Pharmacology, Purdue University, 915 W State St, West Lafayette, Indiana 47907, United States.
  • 3 Life Sciences Institute, Departments of Pharmacology and Biological Chemistry, University of Michigan, 210 Washtenaw Ave, Ann Arbor Michigan 48109, United States.
PMID: 33393767 DOI: 10.1021/acs.jmedchem.0c01522
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.

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