絞り込み

16535

広告

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

著者 Jang J , Son J , Park E , Kosaka T , Saxon JA , De Clercq D , Choi HG , Tanizaki J , Eck MJ , Jänne PA , Gray NS
Angew Chem Int Ed Engl.2018 Jul 06 ; ():.
この記事をPubMed上で見るPubMedで表示
この記事をGoogle翻訳上で見る Google翻訳で開く

スターを付ける スターを付ける     (43view , 0users)

Full Text Sources

Miscellaneous

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 1b 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 1a 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.
PMID: 29978938 [PubMed - as supplied by publisher]
印刷用ページを開く Endnote用テキストダウンロード