posted on 2021-08-31, 15:09authored byRicardo
A. M. Serafim, Fiona J. Sorrell, Benedict-Tilman Berger, Ross J. Collins, Stanley N. S. Vasconcelos, Katlin B. Massirer, Stefan Knapp, James Bennett, Oleg Fedorov, Hitesh Patel, William J. Zuercher, Jonathan M. Elkins
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.