6D8E

Discovery of a Highly Potent and Broadly Effective EGFR and HER2 Exon 20 Insertion Mutant Inhibitor

6D8E の概要

• エントリーDOI: 10.2210/pdb6d8e/pdb
• 分子名称: Epidermal growth factor receptor, (4-fluorophenyl)methyl {2-[(1-methyl-1H-pyrazol-3-yl)amino]pyrimidin-4-yl}[3-(propanoylamino)phenyl]carbamate (3 entities in total)
• 機能のキーワード: egfr, 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: 1
• 化学式量合計: 37793.63

構造登録者

Park, E.,Eck, M.J. (登録日: 2018-04-26, 公開日: 2018-07-18, 最終更新日: 2024-10-16)

主引用文献

Jang, J.,Son, J.,Park, E.,Kosaka, T.,Saxon, J.A.,De Clercq, D.J.H.,Choi, H.G.,Tanizaki, J.,Eck, M.J.,Janne, P.A.,Gray, N.S.
Discovery of a Highly Potent and Broadly Effective Epidermal Growth Factor Receptor and HER2 Exon 20 Insertion Mutant Inhibitor.
Angew. Chem. Int. Ed. Engl., 57:11629-11633, 2018

PubMed Abstract: Exon 20 insertion (Ex20Ins) mutations are the third most prevalent epidermal growth factor receptor (EGFR) activating mutation and the most prevalent HER2 mutation in non-small cell lung cancer (NSCLC). Novel therapeutics for the patients with Ex20Ins mutations are urgently needed, due to their poor responses to the currently approved EGFR and HER2 inhibitors. Here we report the discovery of highly potent and broadly effective EGFR and HER2 Ex20Ins mutant inhibitors. The co-crystal structure of compound 1 b in complex with wild type EGFR clearly revealed an additional hydrophobic interaction of 4-fluorobenzene ring within a deep hydrophobic pocket, which has not been widely exploited in the development of EGFR and HER2 inhibitors. As compared with afatinib, compound 1 a exhibited superior inhibition of proliferation and signaling pathways in Ba/F3 cells harboring either EGFR or HER2 Ex20Ins mutations, and in the EGFR P772_H773insPNP patient-derived lung cancer cell line DFCI127. Our study identifies promising strategies for development of EGFR and HER2 Ex20Ins mutant inhibitors.

PubMed: 29978938
DOI: 10.1002/anie.201805187

実験手法

X-RAY DIFFRACTION (2.537 Å)