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From PIM1 to PI3Kδ via GSK3β: Target Hopping through the Kinome

Authors :
Aurelie C. Champigny
Daniel Thomas
Ian Robert Baldwin
Simon Gaines
Paul Faulder
Benjamin D. Bax
Laura M. Inglesby
Z.A. Henley
Yoshiaki Washio
Joelle Le
Source :
ACS Medicinal Chemistry Letters. 8:1093-1098
Publication Year :
2017
Publisher :
American Chemical Society (ACS), 2017.

Abstract

Selective inhibitors of phosphoinositide 3-kinase delta are of interest for the treatment of inflammatory diseases. Initial optimization of a 3-substituted indazole hit compound targeting the kinase PIM1 focused on improving selectivity over GSK3β through consideration of differences in the ATP binding pockets. Continued kinase cross-screening showed PI3Kδ activity in a series of 4,6-disubstituted indazole compounds, and subsequent structure-activity relationship exploration led to the discovery of an indole-containing lead compound as a potent PI3Kδ inhibitor with selectivity over the other PI3K isoforms.

Details

ISSN :
19485875
Volume :
8
Database :
OpenAIRE
Journal :
ACS Medicinal Chemistry Letters
Accession number :
edsair.doi.dedup.....27f5519d38d282f0bd73dd26004a6f3a