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

• Published in: Journal of medicinal chemistry 2024-03, Vol.67 (5), p.3813-3842
• Main Authors: Rak, Marcel, Menge, Amelie, Tesch, Roberta, Berger, Lena M., Balourdas, Dimitrios-Ilias, Shevchenko, Ekaterina, Krämer, Andreas, Elson, Lewis, Berger, Benedict-Tilman, Abdi, Ismahan, Wahl, Laurenz M., Poso, Antti, Kaiser, Astrid, Hanke, Thomas, Kronenberger, Thales, Joerger, Andreas C., Müller, Susanne, Knapp, Stefan
• Format: Article
• Language: English
• Subjects: Animals; Mammals - metabolism; p21-Activated Kinases; Protein Serine-Threonine Kinases - metabolism
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.3c02217

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.