Discovery of novel 4-arylamino-quinazoline derivatives as EGFRL858R/T790M inhibitors with the potential to inhibit the non-small cell lung cancers.

Three series of quinazoline derivatives (7a-j, 8a-o, 9a-l) were designed and synthesized as EGFRL858R/T790M inhibitors. Series 7a-j and 8a-o are urea and thiourea derivatives while category 9a-l contain the Michael receptor active warhead. Most of the compounds exhibited excellent anti-proliferative activity in vitro against several cancer cell lines, including non-small cell lung cancer (NSCLC) cell lines A549 and H1975, among which 14 compounds had strong antiproliferative activity against A549 and H1975 cancer cells. What's more, they also showed moderate to excellent kinase inhibitory activity against EGFRWT and EGFRL858R/T790M. 8o exhibited the best kinase inhibitory activity with IC50 values of 0.8, 2.7 nM against EGFRWT and EGFRL858R/T790M, respectively. Moreover, AO single staining and Annexin V-FITC/PI staining results also indicated that both 8o and 9b significantly induced apoptosis in A549 cells. 8o arrested the cell cycle at S phase and 9b arrested the cell cycle at G1 phase.