Design and discovery of 4-anilinoquinazoline-acylamino derivatives as EGFR and VEGFR-2 dual TK inhibitors

Both EGFR and VEGFR-2 are important targets for cancer therapy, the combined inhibition of both EGFR and VEGFR-2 signaling pathway represents a promising approach to the treatment of cancers with a synergistic effect. In this study, a series of novel 4-anilinoquinazoline-acylamino derivatives designed as EGFR and VEGFR-2 dual inhibitors were synthesized and evaluated for biological activities. Most of them exhibited interesting inhibitory potencies against EGFR and VEGFR-2 as well as good antiproliferative activities. Compounds 15a, 15b and 15e exhibited the most potent inhibitory activity against EGFR (IC50 = 0.13 mu M, 0.15 mu M and 0.69 mu M, respectively) and VEGFR-2 (IC50 = 0.56 mu M, 1.81 mu M and 0.87 mu M, respectively), among them, compound 15b showed the highest antiproliferative activities against three cancer cell lines (HT-29, MCF-7 and H460) with IC50 of 5.27 mu M, 4.41 mu M and 11.95 mu M, respectively. Molecular docking established the interaction of 15a with the DFG-out conformation of VEGFR-2, suggesting that they might be type II kinase inhibitors. (C) 2015 Elsevier Masson SAS. All rights reserved.