title: Design and discovery of 4-anilinoquinazoline-acylamino derivatives as EGFR and VEGFR-2 dual TK inhibitors.
abstract: 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 μM, 0.15 μM and 0.69 μM, respectively) and VEGFR-2 (IC50 = 0.56 μM, 1.81 μM and 0.87 μM, 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 μM, 4.41 μM and 11.95 μM, 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.
authors.affiliation: Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, PR China; Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, PR China.
authors.forename: Hai-Qi
authors.initials: HQ
authors.lastname: Zhang
authors.affiliation: Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, PR China; Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, PR China.
authors.forename: Fei-Hu
authors.initials: FH
authors.lastname: Gong
authors.affiliation: Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, PR China; Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, PR China.
authors.forename: Chuan-Gui
authors.initials: CG
authors.lastname: Li
authors.affiliation: Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, PR China; Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, PR China.
authors.forename: Chi
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, PR China; Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, PR China.
authors.forename: Yan-Jie
authors.initials: YJ
authors.lastname: Wang
authors.affiliation: Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, PR China; Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, PR China.
authors.forename: Yun-Gen
authors.initials: YG
authors.lastname: Xu
authors.affiliation: Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, PR China; Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, PR China. Electronic address: chslp@cpu.edu.cn.
authors.forename: Li-Ping
authors.initials: LP
authors.lastname: Sun
mesh_terms: D000215:Acylation; D000586:Amination; D000814:Aniline Compounds / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D062105:Molecular Docking Simulation; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D011799:Quinazolines / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000814:Aniline Compounds; D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; C512478:EGFR protein, human; D066246:ErbB Receptors; D040301:Vascular Endothelial Growth Factor Receptor-2
keywords: 4-Anilinoquinazoline-acylamino; Antitumor; EGFR; Tyrosine kinase inhibitor; VEGFR-2