title: SKLB610: a novel potential inhibitor of vascular endothelial growth factor receptor tyrosine kinases inhibits angiogenesis and tumor growth in vivo.
abstract: Antagonizing angiogenesis-related receptor tyrosine kinase is a promising therapeutic strategy in oncology. In present study, we designed and synthesized a novel vascular endothelial growth factor receptor (VEGFR) inhibitor N-methyl-4-(4-(3-(trifluoromethyl) benzamido) phenoxy) picolinamide SKLB610 that potently suppresses human tumor angiogenesis. SKLB610 inhibited angiogenesis-related tyrosine kinase VEGFR2, fibroblast growth factor receptor 2 (FGFR2) and platelet-derived growth factor receptor (PDGFR) at rate of 97%, 65% and 55%, respectively, at concentration of 10μM in biochemical kinase assays. In vitro, SKLB610 showed more selective inhibition of VEGF-stimulated human umbilical vein endothelial cells (HUVECs) proliferation, and this proliferation inhibitory effect was associated with decreased phosphorylation of VEGFR2 and p42/44 mitogen-activated protein kinase (p42/44 MAPK). Antiangiogenic evaluation showed that SKLB610 inhibited the HUVECs capillary-tube formation on Matrigel in vitro and the sub-intestinal vein formation of zebrafish in vivo. Moreover, SKLB610 inhibited a panel of human cancer cells proliferation in a concentration-dependent manner and human non-small cell lung cancer cell line A549 and human colorectal cancer cell line HCT116 were most sensitive to SKLB610 treatment. In vivo, chronic intraperitoneally administration of SKLB610 at dose of 50mg/kg/d resulted in significant inhibition in the growth of established human A549 and HCT116 tumor xenografts in nude mice without exhibit toxicity. Histological analysis showed significant reductions in intratumoral microvessel density (CD31 staining) of 43-55% relative to controls depending on the specific tumor xenografts. In conclusion, the present study demonstrated that SKLB610 exhibited its antitumor activity as a multi-targeted inhibitor with more potent inhibition of VEGFR2 activity. Its potential to be a candidate of anticancer agent is worth being further investigated.
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, #1 Keyuan Road 4/Gaopeng Street, Chengdu, China.
authors.forename: Zhi-Xing
authors.initials: ZX
authors.lastname: Cao
authors.forename: Ren-Lin
authors.initials: RL
authors.lastname: Zheng
authors.forename: Hong-Jun
authors.initials: HJ
authors.lastname: Lin
authors.forename: Shi-Dong
authors.initials: SD
authors.lastname: Luo
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhou
authors.forename: You-Zhi
authors.initials: YZ
authors.lastname: Xu
authors.forename: Xiu-Xiu
authors.initials: XX
authors.lastname: Zeng
authors.forename: Zhao
authors.initials: Z
authors.lastname: Wang
authors.forename: Li-Na
authors.initials: LN
authors.lastname: Zhou
authors.forename: Yong-Qiu
authors.initials: YQ
authors.lastname: Mao
authors.forename: Li
authors.initials: L
authors.lastname: Yang
authors.forename: Yu-Quan
authors.initials: YQ
authors.lastname: Wei
authors.forename: Luo-Ting
authors.initials: LT
authors.lastname: Yu
authors.forename: Sheng-Yong
authors.initials: SY
authors.lastname: Yang
authors.forename: Ying-Lan
authors.initials: YL
authors.lastname: Zhao
mesh_terms: D000577:Amides / Q000138:chemical synthesis / Q000494:pharmacology; D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003094:Collagen / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004338:Drug Combinations; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects; D005260:Female; D006801:Humans; D007797:Laminin / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D010848:Picolinic Acids / Q000138:chemical synthesis / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D011509:Proteoglycans / Q000378:metabolism; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017479:Receptors, Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014471:Umbilical Veins / Q000166:cytology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D015027:Zebrafish
chemical_list: D000577:Amides; D020533:Angiogenesis Inhibitors; D004338:Drug Combinations; D007797:Laminin; D010848:Picolinic Acids; D047428:Protein Kinase Inhibitors; D011509:Proteoglycans; C059485:matrigel; D003094:Collagen; D051497:Receptor, Fibroblast Growth Factor, Type 2; D017479:Receptors, Platelet-Derived Growth Factor; D040301:Vascular Endothelial Growth Factor Receptor-2; D019950:Mitogen-Activated Protein Kinase 1; C003142:picolinamide