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

Research output: Contribution to journalArticle

Authors

External Institution(s)

  • University of Michigan, Ann Arbor
  • Purdue University

Details

Original languageEnglish (US)
Pages (from-to)1628-1634
Number of pages7
JournalACS Medicinal Chemistry Letters
Volume10
Issue number12
StatusPublished - Dec 12 2019
Peer-reviewedYes

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.

    Research areas

  • GPCR kinase, covalent inhibitor, heart failure, kinase inhibitor

Citation formats

APA

Rowlands, R. A., Cato, M. C., Waldschmidt, H. V., Bouley, R. A., Chen, Q., Avramova, L., ... White, A. D. (2019). Structure-Based Design of Selective, Covalent G Protein-Coupled Receptor Kinase 5 Inhibitors. ACS Medicinal Chemistry Letters, 10(12), 1628-1634. https://doi.org/10.1021/acsmedchemlett.9b00365

Harvard

Rowlands, RA, Cato, MC, Waldschmidt, HV, Bouley, RA, Chen, Q, Avramova, L, Larsen, SD, Tesmer, JJG & White, AD 2019, 'Structure-Based Design of Selective, Covalent G Protein-Coupled Receptor Kinase 5 Inhibitors', ACS Medicinal Chemistry Letters, vol. 10, no. 12, pp. 1628-1634. https://doi.org/10.1021/acsmedchemlett.9b00365