Details

Autor(en) / Beteiligte

• 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

Titel

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

Ist Teil von

• Journal of medicinal chemistry, 2024-03, Vol.67 (5), p.3813-3842

Ort / Verlag

United States: American Chemical Society

Erscheinungsjahr

2024

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.