%0 Journal Article
%A Rowlands, Rachel
A.
%A Cato, M. Claire
%A Waldschmidt, Helen V.
%A Bouley, Renee A.
%A Chen, Qiuyan
%A Avramova, Larisa
%A Larsen, Scott D.
%A Tesmer, John J. G.
%A White, Andrew D.
%D 2019
%T Structure-Based
Design of Selective, Covalent G Protein-Coupled Receptor Kinase 5
Inhibitors
%U https://acs.figshare.com/articles/journal_contribution/Structure-Based_Design_of_Selective_Covalent_G_Protein-Coupled_Receptor_Kinase_5_Inhibitors/10305410
%R 10.1021/acsmedchemlett.9b00365.s001
%2 https://acs.figshare.com/ndownloader/files/18727688
%K GRK 5 subfamily
%K GRK 5
%K GPCR
%K G protein-coupled receptor
%K Covalent G Protein-Coupled Receptor Kinase 5 Inhibitors
%K inhibitor
%K GRK 5 drug discovery
%X 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.
%I ACS Publications