10.1021/acsmedchemlett.9b00365.s001 Rachel A. Rowlands Rachel A. Rowlands M. Claire Cato M. Claire Cato Helen V. Waldschmidt Helen V. Waldschmidt Renee A. Bouley Renee A. Bouley Qiuyan Chen Qiuyan Chen Larisa Avramova Larisa Avramova Scott D. Larsen Scott D. Larsen John J. G. Tesmer John J. G. Tesmer Andrew D. White Andrew D. White Structure-Based Design of Selective, Covalent G Protein-Coupled Receptor Kinase 5 Inhibitors American Chemical Society 2019 GRK 5 subfamily GRK 5 GPCR G protein-coupled receptor Covalent G Protein-Coupled Receptor Kinase 5 Inhibitors inhibitor GRK 5 drug discovery 2019-11-14 17:39:34 Journal contribution https://acs.figshare.com/articles/journal_contribution/Structure-Based_Design_of_Selective_Covalent_G_Protein-Coupled_Receptor_Kinase_5_Inhibitors/10305410 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, <b>5</b> and <b>16d</b> that covalently interact with a nonconserved cysteine (Cys474) unique to this subfamily. Compounds <b>5</b> and <b>16d</b> 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.