7VRA

The crystal structure of EGFR T790M/C797S with the inhibitor HC5476

7VRA の概要

• エントリーDOI: 10.2210/pdb7vra/pdb
• 分子名称: Epidermal growth factor receptor, 25-chloro-11-(ethylsulfonyl)-44-morpholino-11H-5,12-dioxa-3-aza-1(3,6)-indola-2(4,2)-pyrimidina-4(1,3)-benzenacyclododecaphane (3 entities in total)
• 機能のキーワード: egfr, inhibitor, complex, transferase, transferase-transferase inhibitor complex, transferase/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: 38072.50

構造登録者

Zhu, S.J. (登録日: 2021-10-22, 公開日: 2022-06-08, 最終更新日: 2023-11-29)

主引用文献

Chen, H.,Lai, M.,Zhang, T.,Chen, Y.,Tong, L.,Zhu, S.,Zhou, Y.,Ren, X.,Ding, J.,Xie, H.,Lu, X.,Ding, K.
Conformational Constrained 4-(1-Sulfonyl-3-indol)yl-2-phenylaminopyrimidine Derivatives as New Fourth-Generation Epidermal Growth Factor Receptor Inhibitors Targeting T790M/C797S Mutations.
J.Med.Chem., 65:6840-6858, 2022

PubMed Abstract: Tertiary C797S mutation of epidermal growth factor receptor (EGFR)-mediated resistance in non-small-cell-lung-cancer (NSCLC) patients is still an unmet clinical need. Several classes of adenosine 5'-triphosphate-competitive or allosteric EGFR inhibitors and degraders have been developed, but none of them have received approval from the regulatory agencies. Herein, we report the structure-based design of conformational constrained 4-(1-ethylsufonyl-3-indolyl)-2-phenylaminopyrimidines as new EGFR inhibitors by using a macrocyclization strategy. Representative compound potently inhibited EGFR and EGFR mutants with IC values of 15.8 and 23.6 nM and suppressed Ba/F3-EGFR and Ba/F3-EGFR cells with IC values of 0.036 and 0.052 μM, respectively, which is 10-20-fold more potent than brigatinib. also potently inhibited the EGFR-mutated PC-9-OR NSCLC cell proliferation with an IC value of 0.644 μM but was less potent for parental Ba/F3 and A431 cells. This study provides a new lead compound for drug discovery to combat EGFR-mediated resistance in NSCLC patients.

PubMed: 35446588
DOI: 10.1021/acs.jmedchem.2c00168

実験手法

X-RAY DIFFRACTION (2.41 Å)