Development of Selective Pyrido[2,3-d]pyrimidin-7(8H)-one-Based Mammalian STE20-Like (MST3/4) Kinase Inhibitors
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:67 |
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| Enthalten in: |
Journal of medicinal chemistry - 67(2024), 5 vom: 14. März, Seite 3813-3842 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Rak, Marcel [VerfasserIn] |
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| Links: |
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| Themen: |
EC 2.7.11.1 |
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| Anmerkungen: |
Date Completed 15.03.2024 Date Revised 15.03.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1021/acs.jmedchem.3c02217 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM369123751 |
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| 245 | 1 | 0 | |a Development of Selective Pyrido[2,3-d]pyrimidin-7(8H)-one-Based Mammalian STE20-Like (MST3/4) Kinase Inhibitors |
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| 520 | |a 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 | ||
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| 700 | 1 | |a Menge, Amelie |e verfasserin |4 aut | |
| 700 | 1 | |a Tesch, Roberta |e verfasserin |4 aut | |
| 700 | 1 | |a Berger, Lena M |e verfasserin |4 aut | |
| 700 | 1 | |a Balourdas, Dimitrios-Ilias |e verfasserin |4 aut | |
| 700 | 1 | |a Shevchenko, Ekaterina |e verfasserin |4 aut | |
| 700 | 1 | |a Krämer, Andreas |e verfasserin |4 aut | |
| 700 | 1 | |a Elson, Lewis |e verfasserin |4 aut | |
| 700 | 1 | |a Berger, Benedict-Tilman |e verfasserin |4 aut | |
| 700 | 1 | |a Abdi, Ismahan |e verfasserin |4 aut | |
| 700 | 1 | |a Wahl, Laurenz M |e verfasserin |4 aut | |
| 700 | 1 | |a Poso, Antti |e verfasserin |4 aut | |
| 700 | 1 | |a Kaiser, Astrid |e verfasserin |4 aut | |
| 700 | 1 | |a Hanke, Thomas |e verfasserin |4 aut | |
| 700 | 1 | |a Kronenberger, Thales |e verfasserin |4 aut | |
| 700 | 1 | |a Joerger, Andreas C |e verfasserin |4 aut | |
| 700 | 1 | |a Müller, Susanne |e verfasserin |4 aut | |
| 700 | 1 | |a Knapp, Stefan |e verfasserin |4 aut | |
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