Referenced in: none

Automatically associated channels: ClC4

Title: A chemical tuned strategy to develop novel irreversible EGFR-TK inhibitors with improved safety and pharmacokinetic profiles.

Authors: Guangxin Xia, Wenteng Chen, Jing Zhang, Jiaan Shao, Yong Zhang, Wei Huang, Leduo Zhang, Weixing Qi, Xing Sun, Bojun Li, Zhixiong Xiang, Chen Ma, Jia Xu, Hailin Deng, Yufeng Li, Ping Li, Hong Miao, Jiansheng Han, YanJun Liu, Jingkang Shen, Yongping Yu

Journal, date & volume: J. Med. Chem., 2014 Dec 11 , 57, 9889-900

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/25409491

Abstract
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 EGFR(WT), EGFR(T790M) 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-EGFR(L858R/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.