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.