6WAK

A crystal structure of EGFR(T790M/V948R) in complex with LN3754

6WAK の概要

• エントリーDOI: 10.2210/pdb6wak/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: cancer, 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: 152097.65

構造登録者

Heppner, D.E.,Eck, M.J. (登録日: 2020-03-25, 公開日: 2021-03-31, 最終更新日: 2023-10-18)

主引用文献

Wittlinger, F.,Heppner, D.E.,To, C.,Gunther, M.,Shin, B.H.,Rana, J.K.,Schmoker, A.M.,Beyett, T.S.,Berger, L.M.,Berger, B.T.,Bauer, N.,Vasta, J.D.,Corona, C.R.,Robers, M.B.,Knapp, S.,Janne, P.A.,Eck, M.J.,Laufer, S.A.
Design of a "Two-in-One" Mutant-Selective Epidermal Growth Factor Receptor Inhibitor That Spans the Orthosteric and Allosteric Sites.
J.Med.Chem., 65:1370-1383, 2022

PubMed Abstract: Inhibitors targeting the epidermal growth factor receptor (EGFR) are an effective therapy for patients with non-small cell lung cancer harboring drug-sensitive activating mutations in the EGFR kinase domain. Drug resistance due to treatment-acquired mutations has motivated the development of successive generations of inhibitors that bind in the ATP site. The third-generation agent osimertinib is now a first-line treatment for this disease. Recently, allosteric inhibitors have been developed to overcome drug-resistant mutations that confer a resistance to osimertinib. Here, we present the structure-guided design and synthesis of a mutant-selective lead compound, which consists of a pyridinyl imidazole-fused benzylisoindolinedione scaffold that simultaneously occupies the orthosteric and allosteric sites. The compound potently inhibits enzymatic activity in L858R/T790M/C797S mutant EGFR (4.9 nM), with a significantly lower activity for wild-type EGFR (47 nM). Additionally, this compound achieves modest cetuximab-independent and mutant-selective cellular efficacies on the L858R (1.2 μM) and L858R/T790M (4.4 μM) variants.

PubMed: 34668706
DOI: 10.1021/acs.jmedchem.1c00848

実験手法

X-RAY DIFFRACTION (2.4 Å)