6P1D

Crystal structure of EGFR with mutant-selective dihydrodibenzodiazepinone allosteric inhibitor

6P1D の概要

• エントリーDOI: 10.2210/pdb6p1d/pdb
• 分子名称: Epidermal growth factor receptor, 10-benzyl-8-fluoro-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one, PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER, ... (5 entities in total)
• 機能のキーワード: egfr, cancer, inhibitor, signaling protein, 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: 4
• 化学式量合計: 152646.18

構造登録者

Heppner, D.E.,Eck, M.J. (登録日: 2019-05-19, 公開日: 2019-12-18, 最終更新日: 2023-10-11)

主引用文献

De Clercq, D.J.H.,Heppner, D.E.,To, C.,Jang, J.,Park, E.,Yun, C.H.,Mushajiang, M.,Shin, B.H.,Gero, T.W.,Scott, D.A.,Janne, P.A.,Eck, M.J.,Gray, N.S.
Discovery and Optimization of Dibenzodiazepinones as Allosteric Mutant-Selective EGFR Inhibitors.
Acs Med.Chem.Lett., 10:1549-1553, 2019

PubMed Abstract: Allosteric kinase inhibitors represent a promising new therapeutic strategy for targeting kinases harboring oncogenic driver mutations in cancers. Here, we report the discovery, optimization, and structural characterization of allosteric mutant-selective EGFR inhibitors comprising a 5,10-dihydro-11-dibenzo[,][1,4]diazepin-11-one scaffold. Our structure-based medicinal chemistry effort yielded an inhibitor () of the EGFR(L858R/T790M) and EGFR(L858R/T790M/C797S) mutants with an IC of ∼10 nM and high selectivity, as assessed by kinome profiling. Further efforts to develop allosteric dibenzodiazepinone inhibitors may serve as the basis for new therapeutic options for targeting drug-resistant EGFR mutations.

PubMed: 31749909
DOI: 10.1021/acsmedchemlett.9b00381

実験手法

X-RAY DIFFRACTION (2.4 Å)