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Development of Selective Pyrido[2,3-d]pyrimidin-7(8H)-one-Based Mammalian STE20-Like (MST3/4) Kinase Inhibitors. 2024
Marcel Rak, and
Amelie Menge, and
Roberta Tesch, and
Lena M Berger, and
Dimitrios-Ilias Balourdas, and
Ekaterina Shevchenko, and
Andreas Krämer, and
Lewis Elson, and
Benedict-Tilman Berger, and
Ismahan Abdi, and
Laurenz M Wahl, and
Antti Poso, and
Astrid Kaiser, and
Thomas Hanke, and
Thales Kronenberger, and
Andreas C Joerger, and
Susanne Müller, and
Stefan Knapp
Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Str. 9, 60438 Frankfurt am Main, Germany.
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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