6S9D

EGFR-KINASE IN COMPLEX WITH COMPOUND 6

6S9D の概要

• エントリーDOI: 10.2210/pdb6s9d/pdb
• 関連するPDBエントリー: 6S9B 6S9C
• 分子名称: Epidermal growth factor receptor, 8-oxa-14,21,23,28-tetraazapentacyclo[23.3.1.02,7.014,22.015,20]nonacosa-1(28),2(7),3,5,15,17,19,21,25(29),26-decaen-24-one, DIMETHYL SULFOXIDE, ... (4 entities in total)
• 機能のキーワード: egf receptor kinase mutant t790m, l858r, inhibitor, transferase
• 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: 37898.95

構造登録者

Bader, G. (登録日: 2019-07-12, 公開日: 2019-11-20, 最終更新日: 2024-05-15)

主引用文献

Engelhardt, H.,Bose, D.,Petronczki, M.,Scharn, D.,Bader, G.,Baum, A.,Bergner, A.,Chong, E.,Dobel, S.,Egger, G.,Engelhardt, C.,Ettmayer, P.,Fuchs, J.E.,Gerstberger, T.,Gonnella, N.,Grimm, A.,Grondal, E.,Haddad, N.,Hopfgartner, B.,Kousek, R.,Krawiec, M.,Kriz, M.,Lamarre, L.,Leung, J.,Mayer, M.,Patel, N.D.,Simov, B.P.,Reeves, J.T.,Schnitzer, R.,Schrenk, A.,Sharps, B.,Solca, F.,Stadtmuller, H.,Tan, Z.,Wunberg, T.,Zoephel, A.,McConnell, D.B.
Start Selective and Rigidify: The Discovery Path toward a Next Generation of EGFR Tyrosine Kinase Inhibitors.
J.Med.Chem., 62:10272-10293, 2019

PubMed Abstract: The epidermal growth factor receptor (EGFR), when carrying an activating mutation like del19 or L858R, acts as an oncogenic driver in a subset of lung tumors. While tumor responses to tyrosine kinase inhibitors (TKIs) are accompanied by marked tumor shrinkage, the response is usually not durable. Most patients relapse within two years of therapy often due to acquisition of an additional mutation in EGFR kinase domain that confers resistance to TKIs. Crucially, oncogenic EGFR harboring both resistance mutations, T790M and C797S, can no longer be inhibited by currently approved EGFR TKIs. Here, we describe the discovery of , which is a noncovalent, wild-type EGFR sparing, macrocyclic TKI. potently inhibits the above-described EGFR variants and induces tumor regressions in a cross-resistant EGFR xenograft model. Key was the identification of a highly selective but moderately potent benzimidazole followed by complete rigidification of the molecule through macrocyclization.

PubMed: 31689114
DOI: 10.1021/acs.jmedchem.9b01169

実験手法

X-RAY DIFFRACTION (2.67 Å)