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 () to selectively target MST3/4. These efforts resulted in the development of MR24 () and MR30 () 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 () 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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Article Synopsis
- Peripheral neuropathies (PNs) affect elderly individuals and are linked to Schwann cell dysfunction and irreversible Wallerian degeneration (WD), with few therapeutic options available.
- The study explored the effects of the chemical inhibitor XMU-MP-1 (XMU) on WD, finding that it inhibited the harmful processes in Schwann cells across multiple research models.
- The research highlights the involvement of the Hippo/MST pathway and suggests that XMU could serve as a new multitargeted treatment strategy for elderly patients suffering from PNs.
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