title: YL529, a novel, orally available multikinase inhibitor, potently inhibits angiogenesis and tumour growth in preclinical models.
abstract: OBJECTIVE
  Targeted chemotherapy using small-molecule inhibitors of angiogenesis and proliferation is a promising strategy for cancer therapy.
  
  
  METHODS
  YL529 was developed via computer-aided drug design, de novo synthesis and high-throughput screening. The biochemical, pharmacodynamic and toxicological profiles of YL529 were investigated using kinase and cell viability assays, a mouse tumour cell-containing alginate bead model, a zebrafish angiogenesis model and several human tumour xenograft models in athymic mice.
  
  
  RESULTS
  In vitro, YL529 selectively inhibited the activities of VEGFR2/VEGFR3 and serine/threonine kinase RAF kinase. YL529 inhibited VEGF165 -induced phosphorylation of VEGFR2, as well as the proliferation, migration, invasion and tube formation of human umbilical vascular endothelial cells. It also significantly blocked vascular formation and angiogenesis in the zebrafish model. Moreover, YL529 strongly attenuated the proliferation of A549 cells by disrupting the RAF/mitogen-activated protein (MAP) or extracellular signal-regulated kinase (Erk) kinase (MEK) kinase kinase/MAPK pathway. Oral administration of YL529 (37.5-150 mg(-1) ·kg(-1) ·day(-1) ) to nude mice bearing established tumour xenografts significantly prevented the growth (60-80%) of A549, SPC-A1, A375, OS-RC-2 and HCT116 tumours without detectable toxicity. YL529 markedly reduced microvessel density and increased tumour cell apoptosis in the tumours formed in mice inoculated with the lung cancer cells, SPC-A1 and A549, and the colon carcinoma cells, HCT116.
  
  
  CONCLUSIONS
  YL529, an orally active multikinase inhibitor, shows therapeutic potential for solid tumours, and warrants further investigation as a possible anticancer agent.
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu, China.
authors.forename: Youzhi
authors.initials: Y
authors.lastname: Xu
authors.forename: Hongjun
authors.initials: H
authors.lastname: Lin
authors.forename: Nana
authors.initials: N
authors.lastname: Meng
authors.forename: Wenjie
authors.initials: W
authors.lastname: Lu
authors.forename: Guobo
authors.initials: G
authors.lastname: Li
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Han
authors.forename: Xiaoyun
authors.initials: X
authors.lastname: Dai
authors.forename: Yong
authors.initials: Y
authors.lastname: Xia
authors.forename: Xiangrong
authors.initials: X
authors.lastname: Song
authors.forename: Shengyong
authors.initials: S
authors.lastname: Yang
authors.forename: Yuquan
authors.initials: Y
authors.lastname: Wei
authors.forename: Luoting
authors.initials: L
authors.lastname: Yu
authors.forename: Yinglan
authors.initials: Y
authors.lastname: Zhao
mesh_terms: D000284:Administration, Oral; D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D000818:Animals; D001557:Benzenesulfonates / Q000138:chemical synthesis / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D003110:Colonic Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology*; D004285:Dogs; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000378:metabolism / Q000517:prevention & control; D010766:Phosphorylation / Q000187:drug effects; D010847:Picolines / Q000138:chemical synthesis / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D023382:Toxicity Tests, Acute; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000473:pathology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D015027:Zebrafish
chemical_list: D020533:Angiogenesis Inhibitors; D001557:Benzenesulfonates; C585837:N-methyl-4-(4-(3-(trifluoromethyl)benzamido)phenoxy)picolinamide4- methylbenzenesulfonate; D010847:Picolines; D040301:Vascular Endothelial Growth Factor Receptor-2; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: YL529; anti-angiogenesis; anti-proliferation; small molecular multikinase inhibitor