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Discovery of a Potent Dual SLK/STK10 Inhibitor Based on a Maleimide Scaffold
- 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.
- Subjects :
- Moesin
Protein Serine-Threonine Kinases
Maleimides
Serine
Structure-Activity Relationship
03 medical and health sciences
0302 clinical medicine
Ezrin
Cell Movement
Radixin
Cell Line, Tumor
Drug Discovery
Humans
Phosphorylation
Threonine
Protein Kinase Inhibitors
030304 developmental biology
chemistry.chemical_classification
0303 health sciences
Aniline Compounds
Binding Sites
Molecular Structure
Chemistry
Kinase
Microfilament Proteins
Cell cycle
3. Good health
Cell biology
Molecular Docking Simulation
HEK293 Cells
Enzyme
030220 oncology & carcinogenesis
Molecular Medicine
Protein Binding
Subjects
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