title: SC-535, a novel oral multikinase inhibitor, showed potent antitumor activity in human melanoma models.
abstract: BACKGROUND
  Melanoma is considered as one of the most aggressive and deadliest cancers and current targeted therapies of melanoma often suffer limited efficacy or drug resistance. Discovery of novel multikinase inhibitors as anti-melanoma drug candidates is still needed.
  
  
  METHODS
  In this investigation, we assessed the in vitro and in vivo anti-melanoma activities of SC-535, which is a novel small molecule multikinase inhibitor discovered by us recently. We analyzed inhibitory effects of SC-535 on various melanoma cell lines and human umbilical vascular endothelial cells (HUVEC) in vitro. Tumor xenografts in athymic mice were used to examine the in vivo activity of SC-535.
  
  
  RESULTS
  SC-535 could efficiently inhibit vascular endothelial growth factor receptor (VEGFR) 1/2/3, B-RAF, and C-RAF kinases. It showed significant antiangiogenic potencies both in vitro and in vivo and considerable anti-proliferative ability against several melanoma cell lines. Oral administration of SC-535 resulted in dose-dependent suppression of tumor growth in WM2664 and C32 xenograft mouse models. Studies of mechanisms of action indicated that SC-535 suppressed the tumor angiogenesis and induced G2/M phase cell cycle arrest in human melanoma cells. SC-535 possesses favorable pharmacokinetic properties.
  
  
  CONCLUSIONS
  All of these results support SC-535 as a potential candidate for clinical studies in patients with melanoma.
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Chen
authors.forename: Pan
authors.initials: P
authors.lastname: Ji
authors.forename: Hui-Wen
authors.initials: HW
authors.lastname: Yang
authors.forename: Ling-Ling
authors.initials: LL
authors.lastname: Yang
authors.forename: Shu
authors.initials: S
authors.lastname: Zhou
authors.forename: Lei
authors.initials: L
authors.lastname: Zhong
authors.forename: Shuang
authors.initials: S
authors.lastname: Ma
authors.forename: Xiao-Yu
authors.initials: XY
authors.lastname: Fu
authors.forename: Chan
authors.initials: C
authors.lastname: Zhou
authors.forename: Guo-Bo
authors.initials: GB
authors.lastname: Li
authors.forename: Ming-Wu
authors.initials: MW
authors.lastname: Zheng
authors.forename: Yu-Quan
authors.initials: YQ
authors.lastname: Wei
authors.forename: Sheng-Yong
authors.initials: SY
authors.lastname: Yang
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000627:therapeutic use* / Q000633:toxicity; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006207:Half-Life; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D059566:M Phase Cell Cycle Checkpoints / Q000187:drug effects; D008297:Male; D008545:Melanoma / Q000188:drug therapy*; D051379:Mice; D008819:Mice, Nude; D018919:Neovascularization, Physiologic / Q000187:drug effects; D010671:Phenylurea Compounds / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000627:therapeutic use* / Q000633:toxicity; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors / Q000378:metabolism; D019908:Proto-Oncogene Proteins c-raf / Q000037:antagonists & inhibitors / Q000378:metabolism; D011720:Pyrazoles / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011743:Pyrimidines / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D014183:Transplantation, Heterologous; D015027:Zebrafish
chemical_list: C582543:1-(4-(1H-pyrazolo(3,4-d)pyrimidin-4-yloxy)phenyl)-3-(4-chloro-3-(trifluoromethyl)phenyl)urea; D000970:Antineoplastic Agents; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D040262:Receptors, Vascular Endothelial Growth Factor; D017346:Protein Serine-Threonine Kinases; D048493:Proto-Oncogene Proteins B-raf; D019908:Proto-Oncogene Proteins c-raf