title: SKLB1002, a novel potent inhibitor of VEGF receptor 2 signaling, inhibits angiogenesis and tumor growth in vivo.
abstract: OBJECTIVE
  VEGF receptor 2 (VEGFR2) inhibitors, as efficient antiangiogenesis agents, have been applied in the cancer treatment. However, currently most of these anticancer drugs suffer some adverse effects. Discovery of novel VEGFR2 inhibitors as anticancer drug candidates is still needed.
  
  
  METHODS
  In this investigation, we adopted a restricted de novo design method to design VEGFR2 inhibitors. We selected the most potent compound SKLB1002 and analyzed its inhibitory effects on human umbilical vein endothelial cells (HUVEC) in vitro. Tumor xenografts in zebrafish and athymic mice were used to examine the in vivo activity of SKLB1002.
  
  
  RESULTS
  The use of the restricted de novo design method indeed led to a new potent VEGFR2 inhibitor, SKLB1002, which could significantly inhibit HUVEC proliferation, migration, invasion, and tube formation. Western blot analysis was conducted, which indicated that SKLB1002 inhibited VEGF-induced phosphorylation of VEGFR2 kinase and the downstream protein kinases including extracellular signal-regulated kinase, focal adhesion kinase, and Src. In vivo zebrafish model experiments showed that SKLB1002 remarkably blocked the formation of intersegmental vessels in zebrafish embryos. It was further found to inhibit a new microvasculature in zebrafish embryos induced by inoculated tumor cells. Finally, compared with the solvent control, administration of 100 mg/kg/d SKLB1002 reached more than 60% inhibition against human tumor xenografts in athymic mice. The antiangiogenic effect was indicated by CD31 immunohistochemical staining and alginate-encapsulated tumor cell assay.
  
  
  CONCLUSIONS
  Our findings suggest that SKLB1002 inhibits angiogenesis and may be a potential drug candidate in anticancer therapy.
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, People's Republic of China.
authors.forename: Shuang
authors.initials: S
authors.lastname: Zhang
authors.forename: Zhixing
authors.initials: Z
authors.lastname: Cao
authors.forename: Hongwei
authors.initials: H
authors.lastname: Tian
authors.forename: Guobo
authors.initials: G
authors.lastname: Shen
authors.forename: Yongping
authors.initials: Y
authors.lastname: Ma
authors.forename: Huanzhang
authors.initials: H
authors.lastname: Xie
authors.forename: Yalin
authors.initials: Y
authors.lastname: Liu
authors.forename: Chengjian
authors.initials: C
authors.lastname: Zhao
authors.forename: Senyi
authors.initials: S
authors.lastname: Deng
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
authors.forename: Renlin
authors.initials: R
authors.lastname: Zheng
authors.forename: Weiwei
authors.initials: W
authors.lastname: Li
authors.forename: Na
authors.initials: N
authors.lastname: Zhang
authors.forename: Shengyong
authors.initials: S
authors.lastname: Liu
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Lixia
authors.initials: L
authors.lastname: Dai
authors.forename: Shuai
authors.initials: S
authors.lastname: Shi
authors.forename: Lin
authors.initials: L
authors.lastname: Cheng
authors.forename: Youli
authors.initials: Y
authors.lastname: Pan
authors.forename: Shan
authors.initials: S
authors.lastname: Feng
authors.forename: Xia
authors.initials: X
authors.lastname: Zhao
authors.forename: Hongxin
authors.initials: H
authors.lastname: Deng
authors.forename: Shengyong
authors.initials: S
authors.lastname: Yang
authors.forename: Yuquan
authors.initials: Y
authors.lastname: Wei
mesh_terms: D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects; D005260:Female; D056945:Hep G2 Cells; D006801:Humans; D008546:Melanoma, Experimental; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D009389:Neovascularization, Pathologic; D018919:Neovascularization, Physiologic / Q000187:drug effects; D011799:Quinazolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects*; D013830:Thiadiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D047368:Tumor Burden / Q000187:drug effects; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D015027:Zebrafish / Q000196:embryology
chemical_list: D020533:Angiogenesis Inhibitors; D011799:Quinazolines; C586326:SKLB1002; D013830:Thiadiazoles; D040301:Vascular Endothelial Growth Factor Receptor-2