Marcel Rak, Amelie Menge, Roberta Tesch, Lena M Berger, Dimitrios-Ilias Balourdas, Ekaterina Shevchenko, Andreas Krämer, Lewis Elson, Benedict-Tilman Berger, Ismahan Abdi, Laurenz M Wahl, Antti Poso, Astrid Kaiser, Thomas Hanke, Thales Kronenberger, Andreas C Joerger, Susanne Müller, Stefan Knapp
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...
February 29, 2024: Journal of Medicinal Chemistry