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

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

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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