8GVJ

Crystal structure of cMET kinase domain bound by D6808

8GVJ の概要

• エントリーDOI: 10.2210/pdb8gvj/pdb
• 分子名称: Hepatocyte growth factor receptor, (1^4Z,5^2E)-6^3-(trifluoromethyl)-5^1,5^6-dihydro-1^1H-8-aza-2(3,6)-quinolina-5(1,3)-pyridazina-1(4,1)-pyrazola-6(1,4)-benzenacyclododecaphane-5^6,7-dione (3 entities in total)
• 機能のキーワード: 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: 35400.87

構造登録者

Chen, Y.H.,Qu, L.Z. (登録日: 2022-09-15, 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 (2.71 Å)