8QLR

Human MST3 (STK24) kinase in complex with inhibitor MR24

8QLR の概要

• エントリーDOI: 10.2210/pdb8qlr/pdb
• 分子名称: 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)
• 機能のキーワード: selective kinase inhibitors, structure-guided drug design, transferase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 70323.50

構造登録者

Balourdas, D.I.,Rak, M.,Knapp, S.,Joerger, A.C.,Structural Genomics Consortium (SGC) (登録日: 2023-09-20, 公開日: 2023-11-08, 最終更新日: 2024-06-19)

主引用文献

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

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: 38422480
DOI: 10.1021/acs.jmedchem.3c02217

実験手法

X-RAY DIFFRACTION (1.85 Å)