2. Academic Validation
  3. Discovery of a Potent Dual SLK/STK10 Inhibitor Based on a Maleimide Scaffold

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

  • J Med Chem. 2021 Sep 23;64(18):13259-13278. doi: 10.1021/acs.jmedchem.0c01579.
Ricardo A M Serafim 1 2,  Fiona J Sorrell 3,  Benedict-Tilman Berger 4 5,  Ross J Collins 6,  Stanley N S Vasconcelos 1 2,  Katlin B Massirer 1 2,  Stefan Knapp 4 5,  James Bennett 3,  Oleg Fedorov 3,  Hitesh Patel 6,  William J Zuercher 7,  Jonathan M Elkins 2 3
Affiliations

Affiliations

  • 1 Center for Medicinal Chemistry (CQMED), Center for Molecular Biology and Genetic Engineering (CBMEG), University of Campinas (UNICAMP), Campinas, SP 13083-875, Brazil.
  • 2 Structural Genomics Consortium, University of Campinas (UNICAMP), Av. Dr. André Tosello, 550, Barão Geraldo, Campinas, SP 13083-886, Brazil.
  • 3 Centre for Medicines Discovery, University of Oxford, Old Road Campus Research Building, Old Road Campus, Roosevelt Drive, Oxford OX3 7DQ, U.K.
  • 4 Structural Genomics Consortium, Johann Wolfgang Goethe University, Buchmann Institute for Molecular Life Sciences, Max-von-Laue-Str. 15, D-60438 Frankfurt am Main, DE, Germany.
  • 5 Institute for Pharmaceutical Chemistry, Johann Wolfgang Goethe University, Max-von-Laue-Str. 9, D-60438 Frankfurt am Main, DE, Germany.
  • 6 Medicines Discovery Institute, School of Biosciences, Cardiff University, Cardiff CF10 3AT, U.K.
  • 7 Structural Genomics Consortium, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.
PMID: 34463505 DOI: 10.1021/acs.jmedchem.0c01579
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.

Figures
Products