5GTY

Crystal structure of EGFR 696-1022 T790M in complex with LXX-6-26

5GTY の概要

• エントリーDOI: 10.2210/pdb5gty/pdb
• 関連するPDBエントリー: 5GMP 5GNK 5GTZ
• 分子名称: 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)
• 機能のキーワード: egfr, t790m, lxx-6-26, inhibitor, transferase
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Cell membrane; Single-pass type I membrane protein. Isoform 2: Secreted: P00533
• タンパク質・核酸の鎖数: 8
• 化学式量合計: 305484.92

構造登録者

Yan, X.E.,Yun, C.H. (登録日: 2016-08-23, 公開日: 2017-09-06, 最終更新日: 2024-10-09)

主引用文献

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

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: 28407693
DOI: 10.18632/oncotarget.15443

実験手法

X-RAY DIFFRACTION (3.14 Å)