8FV3

EGFR(T790M/V948R) in complex with compound 1 (LN4503)

8FV3 の概要

• エントリーDOI: 10.2210/pdb8fv3/pdb
• 分子名称: Epidermal growth factor receptor, MAGNESIUM ION, PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER, ... (5 entities in total)
• 機能のキーワード: inhibitor, transferase
• 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: 152073.60

構造登録者

Ogboo, B.C.,Heppner, D.E. (登録日: 2023-01-18, 公開日: 2024-01-17, 最終更新日: 2024-03-20)

主引用文献

Wittlinger, F.,Ogboo, B.C.,Shevchenko, E.,Damghani, T.,Pham, C.D.,Schaeffner, I.K.,Oligny, B.T.,Chitnis, S.P.,Beyett, T.S.,Rasch, A.,Buckley, B.,Urul, D.A.,Shaurova, T.,May, E.W.,Schaefer, E.M.,Eck, M.J.,Hershberger, P.A.,Poso, A.,Laufer, S.A.,Heppner, D.E.
Linking ATP and allosteric sites to achieve superadditive binding with bivalent EGFR kinase inhibitors.
Commun Chem, 7:38-38, 2024

PubMed Abstract: Bivalent molecules consisting of groups connected through bridging linkers often exhibit strong target binding and unique biological effects. However, developing bivalent inhibitors with the desired activity is challenging due to the dual motif architecture of these molecules and the variability that can be introduced through differing linker structures and geometries. We report a set of alternatively linked bivalent EGFR inhibitors that simultaneously occupy the ATP substrate and allosteric pockets. Crystal structures show that initial and redesigned linkers bridging a trisubstituted imidazole ATP-site inhibitor and dibenzodiazepinone allosteric-site inhibitor proved successful in spanning these sites. The re-engineered linker yielded a compound that exhibited significantly higher potency (~60 pM) against the drug-resistant EGFR L858R/T790M and L858R/T790M/C797S, which was superadditive as compared with the parent molecules. The enhanced potency is attributed to factors stemming from the linker connection to the allosteric-site group and informs strategies to engineer linkers in bivalent agent design.

PubMed: 38378740
DOI: 10.1038/s42004-024-01108-3

実験手法

X-RAY DIFFRACTION (2.1 Å)