7LTX

EGFR (T790M/V948R) in complex with quinazolinone allosteric inhibitor

7LTX の概要

• エントリーDOI: 10.2210/pdb7ltx/pdb
• 分子名称: Epidermal growth factor receptor, PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER, MAGNESIUM ION, ... (5 entities in total)
• 機能のキーワード: egfr, kinase, allosteric, inhibitor, quinazolinone, transferase, transferase-inhibitor complex, transferase/inhibitor
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 155235.00

構造登録者

Beyett, T.S.,Eck, M.J. (登録日: 2021-02-20, 公開日: 2022-02-23, 最終更新日: 2023-10-18)

主引用文献

Gero, T.W.,Heppner, D.E.,Beyett, T.S.,To, C.,Azevedo, S.C.,Jang, J.,Bunnell, T.,Feru, F.,Li, Z.,Shin, B.H.,Soroko, K.M.,Gokhale, P.C.,Gray, N.S.,Janne, P.A.,Eck, M.J.,Scott, D.A.
Quinazolinones as allosteric fourth-generation EGFR inhibitors for the treatment of NSCLC.
Bioorg.Med.Chem.Lett., 68:128718-128718, 2022

PubMed Abstract: The C797S mutation confers resistance to covalent EGFR inhibitors used in the treatment of lung tumors with the activating L858R mutation. Isoindolinones such as JBJ-4-125-02 bind in an allosteric pocket and are active against this mutation, with high selectivity over wild-type EGFR. The most potent examples we developed from that series have a potential chemical instability risk from the combination of the amide and phenol groups. We explored a scaffold hopping approach to identify new series of allosteric EGFR inhibitors that retained good potency in the absence of the phenol group. The 5-F quinazolinone 34 demonstrated tumor regression in an H1975 efficacy model upon once daily oral dosing at 25 mg/kg.

PubMed: 35378251
DOI: 10.1016/j.bmcl.2022.128718

実験手法

X-RAY DIFFRACTION (2.3 Å)