Design, synthesis and biological evaluation of AZD9291 derivatives as selective and potent EGFR<sup>L858R/T790M</sup> inhibitors.
Zhao B, Xiao Z, Qi J, Luo R, Lan Z, Zhang Y, Hu X, Tang Q, Zheng P, Xu S, Zhu W.
Third-generation epidermal growth factor receptor (EGFR)<sup>L858R/T790M</sup> 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 EGFR<sup>L858R/T790M</sup> inhibitors. The most potent compound 18e demonstrated excellent kinase inhibitory activity and selectivity for EGFR<sup>L858R/T790M</sup> double mutants and the IC<sub>50</sub> 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.