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.
Journal article
J Med Chem
23/09/2021
64
13259 - 13278
Aniline Compounds, Binding Sites, Cell Line, Tumor, Cell Movement, HEK293 Cells, Humans, Maleimides, Microfilament Proteins, Molecular Docking Simulation, Molecular Structure, Phosphorylation, Protein Binding, Protein Kinase Inhibitors, Protein Serine-Threonine Kinases, Structure-Activity Relationship