Development of Selective Pyrido[2,3- d]pyrimidin-7(8 H)-one-Based Mammalian STE20-Like (MST3/4) Kinase Inhibitors

  • J Med Chem. 2024 Mar 14;67(5):3813-3842. doi: 10.1021/acs.jmedchem.3c02217.
Marcel Rak  1  2 ,  Amelie Menge  1  2 ,  Roberta Tesch  1  2 ,  Lena M Berger  1  2 ,  Dimitrios-Ilias Balourdas  1  2 ,  Ekaterina Shevchenko  3 ,  Andreas Krämer  1  2  4 ,  Lewis Elson  1  2 ,  Benedict-Tilman Berger  1  2 ,  Ismahan Abdi  1  2 ,  Laurenz M Wahl  1  2 ,  Antti Poso  3  5 ,  Astrid Kaiser  1 ,  Thomas Hanke  1  2 ,  Thales Kronenberger  3  5 ,  Andreas C Joerger  1  2 ,  Susanne Müller  1  2 ,  Stefan Knapp  1  2  4
Affiliations
  • 1. Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Str. 9, 60438 Frankfurt am Main, Germany.
  • 2. Structural Genomics Consortium (SGC), Buchmann Institute for Life Sciences, Max-von-Laue-Str. 15, 60438 Frankfurt am Main, Germany.
  • 3. Institute of Pharmacy, Pharmaceutical/Medicinal Chemistry and Tübingen Center for Academic Drug Discovery (TüCAD2), Eberhard Karls University Tübingen, Auf der Morgenstelle 8, 72076 Tübingen, Germany.
  • 4. German Translational Cancer Network (DKTK) and Frankfurt Cancer Institute (FCI), 60438 Frankfurt am Main, Germany.
  • 5. School of Pharmacy, University of Eastern Finland, Yliopistonranta 1, 70210 Kuopio, Finland.
PMID: 38422480 DOI: 10.1021/acs.jmedchem.3c02217
Abstract

Mammalian STE20-like (MST) kinases 1-4 play key roles in regulating the Hippo and Autophagy pathways, and their dysregulation has been implicated in Cancer development. In contrast to the well-studied MST1/2, the roles of MST3/4 are less clear, in part due to the lack of potent and selective inhibitors. Here, we re-evaluated literature compounds, and used structure-guided design to optimize the p21-activated kinase (PAK) inhibitor G-5555 (8) to selectively target MST3/4. These efforts resulted in the development of MR24 (24) and MR30 (27) with good kinome-wide selectivity and high cellular potency. The distinct cellular functions of closely related MST kinases can now be elucidated with subfamily-selective chemical tool compounds using a combination of the MST1/2 inhibitor PF-06447475 (2) and the two MST3/4 inhibitors developed. We found that MST3/4-selective inhibition caused a cell-cycle arrest in the G1 phase, whereas MST1/2 inhibition resulted in accumulation of cells in the G2/M phase.

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