8QLR
Human MST3 (STK24) kinase in complex with inhibitor MR24
Summary for 8QLR
| Entry DOI | 10.2210/pdb8qlr/pdb |
| Descriptor | Serine/threonine-protein kinase 24, 8-(4-azanylbutyl)-2-[1,3-bis(oxidanyl)propan-2-ylamino]-6-[2-chloranyl-4-(6-methylpyridin-2-yl)phenyl]pyrido[2,3-d]pyrimidin-7-one, 1,2-ETHANEDIOL, ... (4 entities in total) |
| Functional Keywords | selective kinase inhibitors, structure-guided drug design, transferase |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 2 |
| Total formula weight | 70323.50 |
| Authors | Balourdas, D.I.,Rak, M.,Knapp, S.,Joerger, A.C.,Structural Genomics Consortium (SGC) (deposition date: 2023-09-20, release date: 2023-11-08, Last modification date: 2024-06-19) |
| Primary citation | Rak, M.,Menge, A.,Tesch, R.,Berger, L.M.,Balourdas, D.I.,Shevchenko, E.,Kramer, A.,Elson, L.,Berger, B.T.,Abdi, I.,Wahl, L.M.,Poso, A.,Kaiser, A.,Hanke, T.,Kronenberger, T.,Joerger, A.C.,Muller, S.,Knapp, S. Development of Selective Pyrido[2,3- d ]pyrimidin-7(8 H )-one-Based Mammalian STE20-Like (MST3/4) Kinase Inhibitors. J.Med.Chem., 67:3813-3842, 2024 Cited by PubMed 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 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. PubMed: 38422480DOI: 10.1021/acs.jmedchem.3c02217 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.85 Å) |
Structure validation
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