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Discovery of a potent dual SLK/STK10 inhibitor based on a maleimide scaffold

DOI: 10.1021/acs.jmedchem.0c01579 DOI Help

Authors: Ricardo A. M. Serafim (University of Campinas (UNICAMP)) , Fiona J. Sorrell (University of Oxford) , Benedict-Tilman Berger (Johann Wolfgang Goethe University) , Ross J. Collins (Cardiff University) , Stanley N. S. Vasconcelos (University of Campinas (UNICAMP)) , Katlin B. Massirer (niversity of Campinas (UNICAMP)) , Stefan Knapp (Johann Wolfgang Goethe University) , James Bennett (University of Oxford) , Oleg Fedorov (University of Oxford) , Hitesh Patel (Cardiff University) , William J. Zuercher (University of North Carolina at Chapel Hill) , Jonathan M. Elkins (University of Campinas (UNICAMP); University of Oxford)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Journal Of Medicinal Chemistry

State: Published (Approved)
Published: August 2021
Diamond Proposal Number(s): 15433

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.

Journal Keywords: Assays; Inhibitors; Inhibition; Peptides and proteins; Selectivity

Subject Areas: Biology and Bio-materials, Chemistry, Medicine


Instruments: I04-1-Macromolecular Crystallography (fixed wavelength)

Added On: 02/09/2021 08:27

Discipline Tags:

Organic Chemistry Life Sciences & Biotech Health & Wellbeing Drug Discovery Structural biology Chemistry Biochemistry

Technical Tags:

Diffraction Macromolecular Crystallography (MX)