2. Academic Validation
  3. Structure-Based Design of Selective, Covalent G Protein-Coupled Receptor Kinase 5 Inhibitors

Structure-Based Design of Selective, Covalent G Protein-Coupled Receptor Kinase 5 Inhibitors

  • ACS Med Chem Lett. 2019 Nov 12;10(12):1628-1634. doi: 10.1021/acsmedchemlett.9b00365.
Rachel A Rowlands 1,  M Claire Cato 2,  Helen V Waldschmidt 1,  Renee A Bouley 2,  Qiuyan Chen 3,  Larisa Avramova 3,  Scott D Larsen 1,  John J G Tesmer 3,  Andrew D White 1
Affiliations

Affiliations

  • 1 University of Michigan, Vahlteich Medicinal Chemistry Core, College of Pharmacy, 428 Church Street, Ann Arbor, Michigan 48109, United States.
  • 2 University of Michigan, Life Sciences Institute, Departments of Pharmacology and Biological Chemistry, 210 Washtenaw Avenue, Ann Arbor, Michigan 48109, United States.
  • 3 Purdue University, Departments of Biological Sciences and Medicinal Chemistry and Molecular Pharmacology, 915 W State Street, West Lafayette, Indiana 47907, United States.
PMID: 31857838 DOI: 10.1021/acsmedchemlett.9b00365
Abstract

The ability of G protein-coupled receptor (GPCR) kinases (GRKs) to regulate desensitization of GPCRs has made GRK2 and GRK5 attractive targets for treating heart failure and Other Diseases such as Cancer. Although advances have been made toward developing inhibitors that are selective for GRK2, there have been far fewer reports of GRK5 selective compounds. Herein, we describe the development of GRK5 subfamily selective inhibitors, 5 and 16d that covalently interact with a nonconserved cysteine (Cys474) unique to this subfamily. Compounds 5 and 16d feature a highly amenable pyrrolopyrimidine scaffold that affords high nanomolar to low micromolar activity that can be easily modified with Michael acceptors with various reactivities and geometries. Our work thereby establishes a new pathway toward further development of subfamily selective GRK inhibitors and establishes Cys474 as a new and useful covalent handle in GRK5 drug discovery.

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