title: Exploration of acridine scaffold as a potentially interesting scaffold for discovering novel multi-target VEGFR-2 and Src kinase inhibitors.
abstract: VEGFR-2 and Src kinases both play important roles in cancers. In certain cancers, Src works synergistically with VEGFR-2 to promote its activation. Development of multi-target drugs against VEGFR-2 and Src is of therapeutic advantage against these cancers. By using molecular docking and SVM virtual screening methods and based on subsequent synthesis and bioassay studies, we identified 9-aminoacridine derivatives with an acridine scaffold as potentially interesting novel dual VEGFR-2 and Src inhibitors. The acridine scaffold has been historically used for deriving topoisomerase inhibitors, but has not been found in existing VEGFR-2 inhibitors and Src inhibitors. A series of 21 acridine derivatives were synthesized and evaluated for their antiproliferative activities against K562, HepG-2, and MCF-7 cells. Some of these compounds showed better activities against K562 cells in vitro than imatinib. The structure-activity relationships (SAR) of these compounds were analyzed. One of the compounds (7r) showed low μM activity against K562 and HepG-2 cancer cell-lines, and inhibited VEGFR-2 and Src at inhibition rates of 44% and 8% at 50μM, respectively, without inhibition of topoisomerase. Moreover, 10μM compound 7r could reduce the levels of activated ERK1/2 in a time dependant manner, a downstream effector of both VEGFR-2 and Src. Our study suggested that acridine scaffold is a potentially interesting scaffold for developing novel multi-target kinase inhibitors such as VEGFR-2 and Src dual inhibitors.
authors.affiliation: The Guangdong Province Key Laboratory of Chemical Biology, The Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, PR China.
authors.forename: Xudong
authors.initials: X
authors.lastname: Luan
authors.forename: Chunmei
authors.initials: C
authors.lastname: Gao
authors.forename: Nannan
authors.initials: N
authors.lastname: Zhang
authors.forename: Yuzong
authors.initials: Y
authors.lastname: Chen
authors.forename: Qinsheng
authors.initials: Q
authors.lastname: Sun
authors.forename: Chunyan
authors.initials: C
authors.lastname: Tan
authors.forename: Hongxia
authors.initials: H
authors.lastname: Liu
authors.forename: Yibao
authors.initials: Y
authors.lastname: Jin
authors.forename: Yuyang
authors.initials: Y
authors.lastname: Jiang
mesh_terms: D000166:Acridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D000609:Aminoacridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D045744:Cell Line, Tumor; D003198:Computer Simulation; D006801:Humans; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D013329:Structure-Activity Relationship; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019061:src-Family Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: C561100:6-chloro-2-methoxy-N-(2-methoxybenzyl)acridin-9-amine; D000166:Acridines; D000609:Aminoacridines; D047428:Protein Kinase Inhibitors; D040301:Vascular Endothelial Growth Factor Receptor-2; D019061:src-Family Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3