Design, synthesis and biological evaluation of potent epidermal growth factor receptor tyrosine kinase (EGFR-TK) inhibitors against resistance mutation for lung cancer treatment

In this study, we identified a newly synthesized compound 7o with potent inhibition on EGFR primary mutants (L858R, Del19) and drug-resistant mutant T790M with nanomolar IC₅₀ values. 7o showed strong antiproliferative effects against EGFR mutant-driven non-small cell lung Cancer (NSCLC) cells such as H1975, PC-9 and HCC827, over cells expressing EGFR^WT. Molecular docking was performed to investigate the possible binding modes of 7o inside the binding site of EGFR^L858R/T790M and EGFR^WT. Analysis of cell cycle evidenced that 7o induced cell cycle arrest in G1 phases in the EGFR mutant cells, H1975 and PC-9, which resulted in decreased S-phase populations. Moreover, compound 7o induced Cancer cell Apoptosis in in vitro assays. In addition, 7o inhibited cellular phosphorylation of EGFR. In vivo, oral administration of 7o caused rapid tumor regression in H1975 xenograft model. Therefore, 7o might deserve further optimization as Cancer treatment agent for EGFR mutant-driven NSCLC.

Del19; EGFR; Inhibitor; L858R; T790M.