MSC-1186, a Highly Selective Pan-SRPK Inhibitor Based on an Exceptionally Decorated Benzimidazole-Pyrimidine Core

  • J Med Chem. 2022 Dec 14. doi: 10.1021/acs.jmedchem.2c01705.
Martin Schröder  1  2 ,  Matthias Leiendecker  3 ,  Ulrich Grädler  3 ,  Juliane Braun  3 ,  Andreas Blum  3 ,  Marek Wanior  1 ,  Benedict-Tilman Berger  1  2 ,  Andreas Krämer  1  2 ,  Susanne Müller  1  2 ,  Christina Esdar  3 ,  Stefan Knapp  1  2 ,  Timo Heinrich  3
Affiliations
  • 1. SGC Frankfurt, Goethe University Frankfurt, Buchmann Institute for Life Sciences (BMLS), Riedberg Campus, Max-von-Laue-Str. 15, 60438 Frankfurt am Main, Germany.
  • 2. Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Riedberg Campus, Max-von-Laue-Str. 9, 60438 Frankfurt am Main, Germany.
  • 3. Merck Healthcare KGaA, Frankfurter Str. 250, 64293 Darmstadt, Germany.
PMID: 36516476 DOI: 10.1021/acs.jmedchem.2c01705
Abstract

The highly conserved catalytic sites in protein kinases make it difficult to identify ATP competitive inhibitors with kinome-wide selectivity. Serendipitously, during a dedicated fragment campaign for the focal adhesion kinase (FAK), a scaffold that had lost its initial FAK affinity showed remarkable potency and selectivity for serine-arginine-protein kinases 1-3 (SRPK1-3). Non-conserved interactions with the uniquely structured hinge region of the SRPK family were the key drivers of the exclusive selectivity of the discovered fragment hit. Structure-guided medicinal chemistry efforts led to the SRPK Inhibitor MSC-1186, which fulfills all hallmarks of a reversible chemical probe, including nanomolar cellular potency and excellent kinome-wide selectivity. The combination of MSC-1186 with CDC2-like kinase (CLK) inhibitors showed additive attenuation of SR-protein phosphorylation compared to the single agents. MSC-1186 and negative control (MSC-5360) are chemical probes available via the Structural Genomics Consortium chemical probe program (https://www.sgc-ffm.uni-frankfurt.de/).

Products