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

  • J Med Chem. 2014 Dec 11;57(23):9889-900. doi: 10.1021/jm5014659.
Guangxin Xia  1 ,  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
Affiliations
  • 1. Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Science, Zhejiang University , 866 Yuhangtang Road Zijin Campus, Hangzhou 310058, China.
PMID: 25409491 DOI: 10.1021/jm5014659
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.