7Y4U
Crystal structure of cMET kinase domain bound by compound 9Y
Summary for 7Y4U
| Entry DOI | 10.2210/pdb7y4u/pdb |
| Descriptor | 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) |
| Functional Keywords | transferase inhibitor, transferase, transferase-inhibitor complex, transferase/inhibitor |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 35374.84 |
| Authors | Qu, L.Z.,Chen, Y.H. (deposition date: 2022-06-16, release date: 2022-11-23, Last modification date: 2023-11-29) |
| Primary citation | 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 Cited by 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: 36355693DOI: 10.1021/acs.jmedchem.2c00981 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.26 Å) |
Structure validation
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