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Discovery of a Potent Dual SLK/STK10 Inhibitor Based on a Maleimide Scaffold

Authors :
Stanley Nunes Siqueira Vasconcelos
Katlin B. Massirer
Ricardo A. M. Serafim
Hitesh Patel
Jim Bennett
Oleg Fedorov
Stefan Knapp
Benedict-Tilman Berger
William J. Zuercher
Ross J. Collins
Jonathan M. Elkins
F.J. Sorrell
Source :
Journal of Medicinal Chemistry. 64:13259-13278
Publication Year :
2021
Publisher :
American Chemical Society (ACS), 2021.

Abstract

SLK (STE20-like kinase) and STK10 (serine/threonine kinase 10) are closely related kinases whose enzymatic activity is linked to the regulation of ezrin, radixin, and moesin function and to the regulation of lymphocyte migration and the cell cycle. We identified a series of 3-anilino-4-arylmaleimides as dual inhibitors of SLK and STK10 with good kinome-wide selectivity. Optimization of this series led to multiple SLK/STK10 inhibitors with nanomolar potency. Crystal structures of exemplar inhibitors bound to SLK and STK10 demonstrated the binding mode of the inhibitors and rationalized their selectivity. Cellular target engagement assays demonstrated the binding of the inhibitors to SLK and STK10 in cells. Further selectivity analyses, including analysis of activity of the reported inhibitors against off-targets in cells, identified compound 31 as the most potent and selective inhibitor of SLK and STK10 yet reported.

Details

ISSN :
15204804 and 00222623
Volume :
64
Database :
OpenAIRE
Journal :
Journal of Medicinal Chemistry
Accession number :
edsair.doi.dedup.....aa29241ce6a03c4de90d4ac1d4c2817a
Full Text :
https://doi.org/10.1021/acs.jmedchem.0c01579