Open AccessStructure-Based Design of Selective, Covalent G Protein-Coupled Receptor Kinase 5 Inhibitors
Author(s) -
Rachel A. Rowlands,
M.C. Cato,
Helen V. Waldschmidt,
Renee Bouley,
Qiuyan Chen,
Larisa Avramova,
Scott D. Larsen,
John J.G. Tesmer,
Andrew D. White
Publication year - 2019
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/acsmedchemlett.9b00365
Subject(s) - g protein coupled receptor kinase , g protein coupled receptor , beta adrenergic receptor kinase , subfamily , kinase , covalent bond , drug discovery , chemistry , cysteine , biochemistry , computational biology , drug development , receptor , pharmacology , biology , drug , enzyme , gene , organic chemistry
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.