8A2A

EGFR kinase domain in complex with 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[6-[2-[4-[[4-(hydroxymethyl)-1-piperidyl]methyl]phenyl]ethynyl]-1-oxo-4-(trifluoromethyl)isoindolin-2-yl]-N-thiazol-2-yl-acetamide (form 2)

8A2A の概要

• エントリーDOI: 10.2210/pdb8a2a/pdb
• 関連するPDBエントリー: 8A27
• 分子名称: Epidermal growth factor receptor, (2R)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[5-[2-[4-[[4-(hydroxymethyl)piperidin-1-yl]methyl]phenyl]ethynyl]-3-oxidanylidene-7-(trifluoromethyl)-1H-isoindol-2-yl]-N-(1,3-thiazol-2-yl)ethanamide, SULFATE ION, ... (4 entities in total)
• 機能のキーワード: kinase inhibitor, transferase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 37995.90

構造登録者

Kuglstatter, A.,Ehler, A. (登録日: 2022-06-03, 公開日: 2022-10-19, 最終更新日: 2024-01-31)

主引用文献

Obst-Sander, U.,Ricci, A.,Kuhn, B.,Friess, T.,Koldewey, P.,Kuglstatter, A.,Hewings, D.,Goergler, A.,Steiner, S.,Rueher, D.,Imhoff, M.P.,Raschetti, N.,Marty, H.P.,Dietzig, A.,Rynn, C.,Ehler, A.,Burger, D.,Kornacker, M.,Schaffland, J.P.,Herting, F.,Pao, W.,Bischoff, J.R.,Martoglio, B.,Alice Nagel, Y.,Jaeschke, G.
Discovery of Novel Allosteric EGFR L858R Inhibitors for the Treatment of Non-Small-Cell Lung Cancer as a Single Agent or in Combination with Osimertinib.
J.Med.Chem., 65:13052-13073, 2022

PubMed Abstract: Addressing resistance to third-generation EGFR TKIs such as osimertinib via the EGFR mutation remains a highly unmet need in EGFR-driven non-small-cell lung cancer (NSCLC). Herein, we present the discovery of the allosteric EGFR inhibitor , a novel fourth-generation inhibitor to overcome EGFR-mediated resistance in patients harboring the activating EGFR mutation. exhibits an improved potency compared to previous allosteric EGFR inhibitors. To our knowledge, is the first allosteric EGFR inhibitor that demonstrates robust tumor regression in a mutant EGFR tumor model. Additionally, is active in an H1975 EGFR NSCLC xenograft model and shows superior efficacy in combination with osimertinib compared to the single agents. Our data highlight the potential of as a single agent against EGFR and EGFR and as combination therapy for EGFR- and EGFR-driven NSCLC.

PubMed: 36178776
DOI: 10.1021/acs.jmedchem.2c00893

実験手法

X-RAY DIFFRACTION (1.43 Å)