5GNK
Crystal structure of EGFR 696-988 T790M in complex with LXX-6-34
Summary for 5GNK
| Entry DOI | 10.2210/pdb5gnk/pdb |
| Related | 5GMP |
| Descriptor | Epidermal growth factor receptor, 1-[(3R)-3-[4-azanyl-3-[3-chloranyl-4-[(1-methylimidazol-2-yl)methoxy]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]prop-2-en-1-one, NITRATE ION, ... (6 entities in total) |
| Functional Keywords | egfr, t790m, lxx-6-34, inhibitor, transferase |
| Biological source | Homo sapiens (Human) |
| Cellular location | Cell membrane; Single-pass type I membrane protein. Isoform 2: Secreted: P00533 |
| Total number of polymer chains | 1 |
| Total formula weight | 36202.71 |
| Authors | |
| Primary citation | Wang, A.,Li, X.,Wu, H.,Zou, F.,Yan, X.E.,Chen, C.,Hu, C.,Yu, K.,Wang, W.,Zhao, P.,Wu, J.,Qi, Z.,Wang, W.,Wang, B.,Wang, L.,Ren, T.,Zhang, S.,Yun, C.H.,Liu, J.,Liu, Q. Discovery of (R)-1-(3-(4-Amino-3-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one (CHMFL-EGFR-202) as a Novel Irreversible EGFR Mutant Kinase Inhibitor with a Distinct Binding Mode. J. Med. Chem., 60:2944-2962, 2017 Cited by PubMed Abstract: On the basis of Ibrutinib's core pharmacophore, which was moderately active to EGFR T790M mutant, we discovered novel epidermal growth factor receptor (EGFR) inhibitor compound 19 (CHMFL-EGFR-202), which potently inhibited EGFR primary mutants (L858R, del19) and drug-resistant mutant L858R/T790M. Compound 19 displayed a good selectivity profile among 468 kinases/mutants tested in the KINOMEscan assay (S score (1) = 0.02). In particular, it did not exhibit apparent activities against INSR and IGF1R kinases. The X-ray crystal structure revealed that this class of inhibitors formed a covalent bond with Cys797 in a distinct "DFG-in-C-helix-out" inactive EGFR conformation. Compound 19 displayed strong antiproliferative effects against EGFR mutant-driven nonsmall cell lung cancer (NSCLC) cell lines such as H1975, PC9, HCC827, and H3255 but not the wild-type EGFR expressing cells. In the H1975 and PC9 cell-inoculated xenograft mouse models, compound 19 exhibited dose-dependent tumor growth suppression efficacy without obvious toxicity. Compound 19 might be a potential drug candidate for EGFR mutant-driven NSCLC. PubMed: 28282122DOI: 10.1021/acs.jmedchem.6b01907 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.796 Å) |
Structure validation
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