4LI5

EGFR-K IN COMPLEX WITH N-[3-[[5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl]amino]-4-methoxy-phenyl] Prop-2-enamide

4LI5 の概要

• エントリーDOI: 10.2210/pdb4li5/pdb
• 分子名称: Epidermal growth factor receptor, N-(3-{[5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl]amino}-4-methoxyphenyl)propanamide, SODIUM ION, ... (4 entities in total)
• 機能のキーワード: egf receptor kinase, inhibitor, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 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: 1
• 化学式量合計: 37839.15

構造登録者

Debreczeni, J.E.,Seiffert, G.B.,Kiefersauer, R.,Augustin, M.,Nagel, S.,Ward, R.,Anderton, M.,Ashton, S.,Bethel, P.,Box, M.,Butterworth, S.,Colclough, N.,Chroley, C.,Chuaqui, C.,Cross, D.,Eberlein, C.,Finlay, R.,Hill, G.,Grist, M.,Klinowska, T.,Lane, C.,Martin, S.,Orme, J.,Smith, P.,Wang, F.,Waring, M. (登録日: 2013-07-02, 公開日: 2013-08-28, 最終更新日: 2024-02-28)

主引用文献

Ward, R.A.,Anderton, M.J.,Ashton, S.,Bethel, P.A.,Box, M.,Butterworth, S.,Colclough, N.,Chorley, C.G.,Chuaqui, C.,Cross, D.A.,Dakin, L.A.,Debreczeni, J.E.,Eberlein, C.,Finlay, M.R.,Hill, G.B.,Grist, M.,Klinowska, T.C.,Lane, C.,Martin, S.,Orme, J.P.,Smith, P.,Wang, F.,Waring, M.J.
Structure- and Reactivity-Based Development of Covalent Inhibitors of the Activating and Gatekeeper Mutant Forms of the Epidermal Growth Factor Receptor (EGFR).
J.Med.Chem., 56:7025-7048, 2013

PubMed Abstract: A novel series of small-molecule inhibitors has been developed to target the double mutant form of the epidermal growth factor receptor (EGFR) tyrosine kinase, which is resistant to treatment with gefitinib and erlotinib. Our reported compounds also show selectivity over wild-type EGFR. Guided by molecular modeling, this series was evolved to target a cysteine residue in the ATP binding site via covalent bond formation and demonstrates high levels of activity in cellular models of the double mutant form of EGFR. In addition, these compounds show significant activity against the activating mutations, which gefitinib and erlotinib target and inhibition of which gives rise to their observed clinical efficacy. A glutathione (GSH)-based assay was used to measure thiol reactivity toward the electrophilic functionality of the inhibitor series, enabling both the identification of a suitable reactivity window for their potency and the development of a reactivity quantitative structure-property relationship (QSPR) to support design.

PubMed: 23930994
DOI: 10.1021/jm400822z

実験手法

X-RAY DIFFRACTION (2.64 Å)