Design, synthesis and biological evaluation of AZD9291 derivatives as selective and potent EGFRL858R/T790M inhibitors

• DOI: 10.1016/j.ejmech.2018.11.069
• Publication Date: 2018-12-01T22:16:54Z
• Authors: Bingbing Zhao; Zhen Xiao; Jianguo Qi; Rong Luo; Zhou Lan; Yanzhuo Zhang; Xiaohan Hu; Qidong Tang; Pengwu Zheng; Shan Xu; Wufu Zhu
• Keywords: T790M; EGFR Inhibitors; Lead compound; IC50

Third-generation epidermal growth factor receptor (EGFR)L858R/T790M inhibitors are still the main drugs for the treatment of advanced non-small cell lung cancer (NSCLC), and these drugs have achieved remarkable clinical efficacy. However, there are still many patients suffering from drug-resistant mutations and drug side effects caused by NSCLC. In this study, guided by the molecular simulation, we applied a structure-based drug design strategy (SBDD) and optimized the structure to obtain a series of potent and selective EGFRL858R/T790M inhibitors. The most potent compound 18e demonstrated excellent kinase inhibitory activity and selectivity for EGFRL858R/T790M double mutants and the IC50 value reached nanomolar level. The selectivity of 18e against wild-type EGFR was near to 200-fold. In addition, compound 18e also inhibited H1975 cells proliferation at G2/M phase and induced apoptosis at a concentration of 0.25 μM, which makes it more valuable for potential lung cancer research.