125969-54-2Relevant articles and documents
A chemical tuned strategy to develop novel irreversible EGFR-TK inhibitors with improved safety and pharmacokinetic profiles
Xia, Guangxin,Chen, Wenteng,Zhang, Jing,Shao, Jiaan,Zhang, Yong,Huang, Wei,Zhang, Leduo,Qi, Weixing,Sun, Xing,Li, Bojun,Xiang, Zhixiong,Ma, Chen,Xu, Jia,Deng, Hailin,Li, Yufeng,Li, Ping,Miao, Hong,Han, Jiansheng,Liu, Yanjun,Shen, Jingkang,Yu, Yongping
, p. 9889 - 9900 (2015/02/02)
Gatekeeper T790 M mutation in EGFR is the most prevalent factor underlying acquired resistance. Acrylamide-bearing quinazoline derivatives are powerful irreversible inhibitors for overcoming resistance. Nevertheless, concerns about the risk of nonspecific covalent modification have motivated the development of novel cysteine-targeting inhibitors. In this paper, we demonstrate that fluoro-substituted olefins can be tuned to alter Michael addition reactivity. Incorporation of these olefins into the quinazoline templates produced potent EGFR inhibitors with improved safety and pharmacokinetic properties. A lead compound 5a was validated against EGFRWT, EGFRT790M as well as A431 and H1975 cancer cell lines. Additionally, compound 5a displayed a weaker inhibition against the EGFR-independent cancer cell line SW620 when compared with afatinib. Oral administration of 5a at a dose of 30 mg/kg induced tumor regression in a murine-EGFRL858R/T790M driven H1975 xenograft model. Also, 5a exhibited improved oral bioavailability and safety as well as favorable tissue distribution properties and enhanced brain uptake. These findings provide the basis of a promising strategy toward the treatment of NSCLC patients with drug resistance.
