title: Preclinical anti-angiogenesis and anti-tumor activity of SIM010603, an oral, multi-targets receptor tyrosine kinases inhibitor.
abstract: OBJECTIVE
  SIM010603 is a structurally novel, oral, multi-targeted receptor tyrosine kinase inhibitor. This study investigated the anti-angiogenic and anti-tumor effects of SIM010603.
  
  
  METHODS
  A radiometric protein kinase assay was used for measuring the kinase activity of the 32 protein kinases. Receptor phosphorylation was determined by enzyme-linked immunosorbent assay (ELISA). Cell proliferation was measured by 3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. Cell chemotaxis was evaluated by modified Boyden chamber assay. Effect of SIM010603 on angiogenesis was examined by mouse cornea angiogenesis assay. Effect of SIM010603 on xenografts was assessed by tumor growth delay. Effects of SIM010603 on tumor microvascular density (MVD), recruitment of pericytes, and pericyte encapsulation of tumor vessels were analyzed by immunofluorescent staining technique.
  
  
  RESULTS
  SIM010603 inhibited stem cell factor receptor (Kit), vascular endothelial growth factor receptor-2 (VEGFR-2), platelet-derived growth factor receptor-β (PDGFR-β), glial cell line-derived neurotrophic factor receptor (Rearranged during Transfection; RET), and Fms-like tyrosine kinase-3 (FLT3) with IC(50) values between 5.0 and 68.1 nmol/l. SIM010603 inhibited the phosphorylation of PDGFR-β and VEGFR-2. Moreover, SIM010603 inhibited endothelial cell proliferation, endothelial cells chemotaxis, and corneal angiogenesis. Although SIM010603 exhibited lower activity in regard to proliferation of NCI-H460, MDA-MB-435, and T241-VEGF-A cells (IC(50) > 1 μmol/l), SIM010603 inhibited tumor growth in these xenograft tumor growth models. SIM010603 reduced tumor MVD in T241-VEGF-A tumor xenograft models and decreased positive signals of CD31, NG2 in MDA-MB-435, and LLC-SW-44 xenograft tumor models.
  
  
  CONCLUSIONS
  These results support the clinical assessment of SIM010603 as a therapeutic agent for cancer.
authors.affiliation: Jiangsu Center for Drug Screening, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China.
authors.forename: Dongchun
authors.initials: D
authors.lastname: Wang
authors.forename: Feng
authors.initials: F
authors.lastname: Tang
authors.forename: Sen
authors.initials: S
authors.lastname: Wang
authors.forename: Zhenzhou
authors.initials: Z
authors.lastname: Jiang
authors.forename: Luyong
authors.initials: L
authors.lastname: Zhang
mesh_terms: D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003315:Cornea / Q000098:blood supply / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay; D005021:Ethylamines / Q000008:administration & dosage / Q000494:pharmacology*; D005260:Female; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D005021:Ethylamines; D007211:Indoles; C570037:N-(2-(diethylamino)ethyl)-2-methyl-7-(1,2-dihydro-5-fluoro-2-oxo-3H-indol-3-ylidene)-4,5,6,7-tetrahydro-1H-indole-3-carboxamide; D047428:Protein Kinase Inhibitors; D020797:Receptor, Platelet-Derived Growth Factor beta; D040301:Vascular Endothelial Growth Factor Receptor-2