title: DW10075, a novel selective and small-molecule inhibitor of VEGFR, exhibits antitumor activities both in vitro and in vivo.
abstract: OBJECTIVE
  Targeting the VEGF/VEGF receptor (VEGFR) pathway has proved to be an effective antiangiogenic approach for cancer treatment. Here, we identified 6-((2-((3-acetamidophenyl)amino)pyrimidin-4-yl)oxy)-N-phenyl-1-naphthamide (designated herein as DW10075) as a novel and highly selective inhibitor of VEGFRs.
  
  
  METHODS
  In vitro tyrosine kinase activity was measured using ELISA, and intracellular signaling pathway proteins were detected by Western blot analysis. Endothelial cell proliferation was examined with CCK-8 assays, and tumor cell proliferation was determined with SRB assays. Cell migration, tube formation and rat aortic ring assays were used to detect antiangiogenic activity. Antitumor efficacy was further evaluated in U87-MG human glioblastoma xenograft tumors in nude mice receiving DW10075 (500 mg · kg(-1) · d(-1), po) for two weeks.
  
  
  RESULTS
  Among a panel of 21 kinases tested, DW10075 selectively inhibited VEGFR-1, VEGFR-2 and VEGFR-3 (the IC50 values were 6.4, 0.69 and 5.5 nmol/L, respectively), but did not affect 18 other kinases including FGFR and PDGFR at 10 μmol/L. DW10075 significantly blocked VEGF-induced activation of VEGFR and its downstream signaling transduction in primary human umbilical vein endothelial cells (HUVECs), thus inhibited VEGF-induced HUVEC proliferation. DW10075 (1-100 nmol/L) dose-dependently inhibited VEGF-induced HUVEC migration and tube formation and suppressed angiogenesis in both the rat aortic ring model and the chicken chorioallantoic membrane model. Furthermore, DW10075 exhibited anti-proliferative activity against 22 different human cancer cell lines with IC50 values ranging from 2.2 μmol/L (for U87-MG human glioblastoma cells) to 22.2 μmol/L (for A375 melanoma cells). In U87-MG xenograft tumors in nude mice, oral administration of DW10075 significantly suppressed tumor growth, and reduced the expression of CD31 and Ki67 in the tumor tissues.
  
  
  CONCLUSIONS
  DW10075 is a potent and highly selective inhibitor of VEGFR that deserves further development.
authors.affiliation: Pharmacology and Safety Evaluation Key Laboratory of Tibetan Medicine in Qinghai Province, Northwest Institute of Plateau Biology, Chinese Academy of Sciences, Xining 810008, China.|Division of Antitumor Pharmacology and Department of Medicinal Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.|University of Chinese Academy of Sciences, Beijing 100049, China.
authors.forename: Meng-yuan
authors.initials: MY
authors.lastname: Li
authors.affiliation: Department of Medicinal Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Yong-cong
authors.initials: YC
authors.lastname: Lv
authors.affiliation: Division of Antitumor Pharmacology and Department of Medicinal Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Lin-jiang
authors.initials: LJ
authors.lastname: Tong
authors.affiliation: Division of Antitumor Pharmacology and Department of Medicinal Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Peng
authors.affiliation: Division of Antitumor Pharmacology and Department of Medicinal Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.|University of Chinese Academy of Sciences, Beijing 100049, China.
authors.forename: Rong
authors.initials: R
authors.lastname: Qu
authors.affiliation: University of Chinese Academy of Sciences, Beijing 100049, China.|Shanghai Tech University, Shanghai 200120, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Division of Antitumor Pharmacology and Department of Medicinal Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Yi-ming
authors.initials: YM
authors.lastname: Sun
authors.affiliation: Division of Antitumor Pharmacology and Department of Medicinal Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Pharmacology and Safety Evaluation Key Laboratory of Tibetan Medicine in Qinghai Province, Northwest Institute of Plateau Biology, Chinese Academy of Sciences, Xining 810008, China.|University of Chinese Academy of Sciences, Beijing 100049, China.
authors.forename: Li-xin
authors.initials: LX
authors.lastname: Wei
authors.affiliation: Division of Antitumor Pharmacology and Department of Medicinal Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Mei-yu
authors.initials: MY
authors.lastname: Geng
authors.affiliation: Department of Medicinal Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Wen-hu
authors.initials: WH
authors.lastname: Duan
authors.affiliation: Division of Antitumor Pharmacology and Department of Medicinal Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Hua
authors.initials: H
authors.lastname: Xie
authors.affiliation: Division of Antitumor Pharmacology and Department of Medicinal Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Ding
mesh_terms: D020533:Angiogenesis Inhibitors / Q000737:chemistry* / Q000627:therapeutic use*; D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002645:Chickens; D005909:Glioblastoma / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009369:Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D011743:Pyrimidines / Q000737:chemistry* / Q000627:therapeutic use*; D017207:Rats, Sprague-Dawley; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; D011743:Pyrimidines; D040262:Receptors, Vascular Endothelial Growth Factor