7Y4U

Crystal structure of cMET kinase domain bound by compound 9Y

7Y4U の概要

• エントリーDOI: 10.2210/pdb7y4u/pdb
• 分子名称: Hepatocyte growth factor receptor, ~{N}-methyl-4-[1-[2-[3-(1-methylpyrazol-4-yl)quinolin-6-yl]ethyl]-6-oxidanylidene-pyridazin-3-yl]-2-(trifluoromethyl)benzamide (3 entities in total)
• 機能のキーワード: transferase inhibitor, transferase, transferase-inhibitor complex, transferase/inhibitor
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 35374.84

構造登録者

Qu, L.Z.,Chen, Y.H. (登録日: 2022-06-16, 公開日: 2022-11-23, 最終更新日: 2023-11-29)

主引用文献

Wang, C.,Li, J.,Qu, L.,Tang, X.,Song, X.,Yang, F.,Chen, X.,Lin, Q.,Lin, W.,Zhou, Y.,Tu, Z.,Chen, Y.,Zhang, Z.,Lu, X.
Discovery of D6808, a Highly Selective and Potent Macrocyclic c-Met Inhibitor for Gastric Cancer Harboring MET Gene Alteration Treatment.
J.Med.Chem., 65:15140-15164, 2022

PubMed Abstract: alterations have been validated as a driven factor in NSCLC and gastric cancers. The c-Met inhibitors, capmatinib, tepotinib, and savolitinib, are only approved for the treatment of NSCLC harboring exon 14 skipping mutant MET. We used a molecular hybridization in conjunction with macrocyclization strategy for structural optimization to obtain a series of 2-(2-(quinolin-6-yl)ethyl)pyridazin-3(2)-one derivatives as new c-Met inhibitors. One of the macrocyclic compounds, D6808, potently inhibited c-Met kinase and -amplified Hs746T gastric cancer cells with IC values of 2.9 and 0.7 nM, respectively. It also strongly suppressed Ba/F3-Tpr-Met cells harboring resistance-relevant mutations (F1200L/M1250T/H1094Y/F1200I/L1195V) with IC values of 4.2, 3.2, 1.0, 39.0, and 33.4 nM, respectively. Furthermore, D6808 exhibited extraordinary target specificity in a Kinome profiling against 373 wild-type kinases and served as a promising macrocycle-based compound for further anticancer drug development.

PubMed: 36355693
DOI: 10.1021/acs.jmedchem.2c00981

実験手法

X-RAY DIFFRACTION (2.26 Å)