Design And Synthesis Of EGFR Tyrosine Kinase Inhibitors Based Quinazoline

Cancer is a leading cause of death worldwide. In the past decades, researchers from all over the world have tried their best to develop high efficiency and low toxicity anticancer drugs. Overexpression of EGFR has been observed in many human tumors such as NSCLC, breast, head and neck cancers. EGFR plays a vital role in the regulation of cell proliferation, differentiation and survival. Thus, EGFR has been emerging as one of the most effective and attractive therapeutic targets for anti-cancer therapy. Gefitinib and Erlotinib were approved by US FDA in 2002 and 2004, respectively, and have been shown to be particularly beneficial for NSCLC patients. However, emergence of acquired point mutations makes their efficacy diminish eventually. Particularly, a single T790 M point mutation accounts for approximately 50% in clinically acquired resistant patients.Based on the review of the development of marketed or in clinical EGFR inhibitors and binding model in the literature, we designed and synthesized three series of 4-anilinoquinazoline derivatives, totally 87 newly compounds, as EGFR tyrosine kinase inhibitors.Firstly, a novel series of 2,3-dihydro-[1,4]dioxino[2,3-f]quinazoline derivatives were designed and synthesized. Most of the compounds exhibited good potency against EGFRwt and some showed moderate to excellent potency against EGFRT790M/L858 R mutate. The half-maximal inhibitory concentration(IC50) values of twenty-one compounds against EGFRwt were less than 50 n M. The IC50 values of eleven compounds against EGFRT790M/L858 R were less than 100 n M. Among these, compound 29b1 displayed the most potent inhibitory activity against EGFRwt(IC50 = 2 n M) and EGFRT790M/L858R(IC50 = 6.88 n M). Compounds with better EGFRwt and EGFRT790M/L858 R kinase inhibitory activities showed well antiproliferative activities against H358 and A549 cells and displayed low toxicity against T293 cell.Continue investigations resulted in the discovery of a series of novel 3-(methoxymethyl)-2,3-dihydro-[1,4]dioxino[2,3-f]quinazolin-10-amine derivatives as EGFR inhibitors. All of the twenty-two newly synthesized compounds showed good inhibitory activities against EGFRwt with IC50 values ranging from 10.29 n M to 652.3 n M. In particular, 47 b, 47 c, 48 b and 48 c showed superb potency, which was comparable to that of the positive control Erlotinib and Gefitinib. Most of the tested compounds were particularly active at blocking proliferation of A549 and H157 cells and displayed low cytotoxicity in vitro against T293 cells.And then a series of novel morpholin-3-one-fused quinazoline derivatives were designed, synthesized and evaluated as EGFR tyrosine kinase inhibitors. Nineteen compounds showed significant inhibitory activities against EGFRwt kinase(53.1 n M ≤ IC50 ≤ 830 n M). Compound 60a8 demonstrated the most potent inhibitory activity toward EGFRwt(IC50 = 53.1 n M). Compound 60a7 and 60a8 showed excellent inhibitory activities against mutant EGFRT790M/L858 R and strong antiproliferative activity against H358 and A549 cells.Finally, 81 of the target compounds were chosen to do 3D-QSAR and molecular dynamics were done for 29a2. The results would be very useful for designing new series of tyrosine kinase inhibitors targeting EGFR.