5GTY
Crystal structure of EGFR 696-1022 T790M in complex with LXX-6-26
Summary for 5GTY
| Entry DOI | 10.2210/pdb5gty/pdb |
| Related | 5GMP 5GNK 5GTZ |
| Descriptor | Epidermal growth factor receptor, 1-[(3R)-3-[4-azanyl-3-[3-chloranyl-4-[(6-methylpyridin-2-yl)methoxy]phenyl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]prop-2-en-1-one, 1,2-ETHANEDIOL, ... (4 entities in total) |
| Functional Keywords | egfr, t790m, lxx-6-26, 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 | 8 |
| Total formula weight | 305484.92 |
| Authors | |
| Primary citation | Hu, C.,Wang, A.,Wu, H.,Qi, Z.,Li, X.,Yan, X.E.,Chen, C.,Yu, K.,Zou, F.,Wang, W.,Wang, W.,Wu, J.,Liu, J.,Wang, B.,Wang, L.,Ren, T.,Zhang, S.,Yun, C.H.,Liu, J.,Liu, Q. Discovery and characterization of a novel irreversible EGFR mutants selective and potent kinase inhibitor CHMFL-EGFR-26 with a distinct binding mode. Oncotarget, 8:18359-18372, 2017 Cited by PubMed Abstract: EGFR T790M mutation accounts for about 40-55% drug resistance for the first generation EGFR kinase inhibitors in the NSCLC. Starting from ibrutinib, a highly potent irreversible BTK kinase inhibitor, which was also found to be moderately active to EGFR T790M mutant, we discovered a highly potent irreversible EGFR inhibitor CHMFL-EGFR-26, which is selectively potent against EGFR mutants including L858R, del19, and L858R/T790M. It displayed proper selectivity window between the EGFR mutants and the wide-type. CHMFL-EGFR-26 exhibited good selectivity profile among 468 kinases/mutants tested (S score (1)=0.02). In addition, X-ray crystallography revealed a distinct "DFG-in" and "cHelix-out" inactive binding mode between CHMFL-EGFR-26 and EGFR T790M protein. The compound showed highly potent anti-proliferative efficacy against EGFR mutant but not wide-type NSCLC cell lines through effective inhibition of the EGFR mediated signaling pathway, induction of apoptosis and arresting of cell cycle progression. CHMFL-EGFR-26 bore acceptable pharmacokinetic properties and demonstrated dose-dependent tumor growth suppression in the H1975 (EGFR L858R/T790M) and PC-9 (EGFR del19) inoculated xenograft mouse models. Currently CHMFL-EGFR-26 is undergoing extensive pre-clinical evaluation for the clinical trial purpose. PubMed: 28407693DOI: 10.18632/oncotarget.15443 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (3.14 Å) |
Structure validation
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