Development of selective pyridopyrimidin-7(8H)-one-based Mammalian STE20-like (MST3/4) kinase inhibitors

Rak, M.; Menge, A.; Tesch, R.; Berger, L. M.; Balourdas, D.-I.; Shevchenko, E.; Kraemer, A.; Elson, L.; Berger, B.-T.; Abdi, I.; Wahl, L. M.; Poso, A.; Kaiser, A.; Hanke, T.; Kronenberger, T.; Joerger, A. C.; Mueller, S.; Knapp, S.

doi:10.1101/2023.11.24.568596

bioRxiv · 10.1101/2023.11.24.568596

Development of selective pyridopyrimidin-7(8H)-one-based Mammalian STE20-like (MST3/4) kinase inhibitors

Rak, M.·Menge, A.·Tesch, R.·Berger, L. M.·Balourdas, D.-I.·Shevchenko, E.·Kraemer, A.·Elson, L.·Berger, B.-T.·Abdi, I.·Wahl, L. M.·Poso, A.·Kaiser, A.·Hanke, T.·Kronenberger, T.·Joerger, A. C.·Mueller, S.·Knapp, S.

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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 MST3/4 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, high potency for MST3/4, and selectivity towards the closely related MST1/2. In combination with the MST1/2 inhibitor PF-06447475 (2) the two MST3/4 inhibitors can be used to elucidate the multiple roles of MST kinases in cells. We found that MST3/4-selective inhibition caused a cell cycle arrest in the G1 phase, while MST1/2 inhibition resulted in accumulation of cells in the G2/M phase. These data point to distinct functions of these closely related kinases, which can now be addressed with subfamily-selective chemical tool compounds.

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Rak, M., Menge, A., Tesch, R., Berger, L. M., Balourdas, D.-I., Shevchenko, E., Kraemer, A., Elson, L., Berger, B.-T., Abdi, I., Wahl, L. M., Poso, A., Kaiser, A., Hanke, T., Kronenberger, T., Joerger, A. C., Mueller, S., Knapp, S.. 2023-11-25. Development of selective pyridopyrimidin-7(8H)-one-based Mammalian STE20-like (MST3/4) kinase inhibitors. https://doi.org/10.1101/2023.11.24.568596

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