title: In vitro pharmacological characterization of TKI-28, a broad-spectrum tyrosine kinase inhibitor with anti-tumor and anti-angiogenic effects.
abstract: Tyrosine kinases are used as important biomarkers in many tumor types. Preclinical and clinical anti-tumor studies have shown that broadly acting tyrosine kinase inhibitors may be more useful than specific inhibitors, since the former might overcome redundancies and crosstalk in tumor cell growth signaling pathways. Here, we aim to identify a novel potent tyrosine kinase inhibitor. Computer modeling of the pyrido-pyrimidine class compound, TKI-28(6-(2,6-dichlorophenyl)-8-methyl-2-phenylamino-8H-pyrido[2,3-d]pyrimidine-7-one), predicted that the compound would dock well in the ATP pocket of the ErbB-2 tyrosine kinase, yielding a high binding affinity for ErbB receptors. Biochemical studies revealed that TKI-28 potently inhibited the activities of tyrosine kinases such as ErbB-2, EGFR, KDR, PDGFRbeta, c-kit and c-Src, but had little effect on Flt-1 in cell-free system. TKI-28 also efficiently blocked autophosphorylation of the listed receptor tyrosine kinases, and subsequently downregulated phosphorylation of many downstream signaling proteins at the cellular level. TKI-28 exhibited a more potent anti-proliferative activity against EGF- and neuregulin-stimulated SK-OV-3 cells versus serum-stimulated cells, accompanied by apparent induction of apoptosis. Finally, TKI-28 was found to possess anti-angiogenic effects, characterized by inhibition of cell proliferation driven by EGF, VEGF and PDGF, as well as decreased cell migration and tube formation in HMECs. These results collectively highlight the pharmacological characteristics of TKI-28 as a broad-spectrum tyrosine kinase inhibitor, suggesting that it has great potential as an anti-cancer and anti-angiogenesis agent.
authors.affiliation: Division of Anti-tumor Pharmacology, Institute of Materia Medica, Graduate School of the Chinese Academy of Sciences, Zhangjiang, Pu Dong, Shanghai, PR China.
authors.forename: Xiao-Ning
authors.initials: XN
authors.lastname: Guo
authors.forename: Li
authors.initials: L
authors.lastname: Zhong
authors.forename: Jin-Zhi
authors.initials: JZ
authors.lastname: Tan
authors.forename: Jian
authors.initials: J
authors.lastname: Li
authors.forename: Xiao-Min
authors.initials: XM
authors.lastname: Luo
authors.forename: Hua-Liang
authors.initials: HL
authors.lastname: Jiang
authors.forename: Fa-Jun
authors.initials: FJ
authors.lastname: Nan
authors.forename: Li-Ping
authors.initials: LP
authors.lastname: Lin
authors.forename: Xiong-Wen
authors.initials: XW
authors.lastname: Zhang
authors.forename: Jian
authors.initials: J
authors.lastname: Ding
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001665:Binding Sites; D002460:Cell Line; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000166:cytology*; D005260:Female; D006860:Hydrogen Bonding; D066298:In Vitro Techniques; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000517:prevention & control; D010051:Ovarian Neoplasms / Q000473:pathology; D011485:Protein Binding; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000145:classification / Q000378:metabolism / Q000494:pharmacology*; D041701:Swiss 3T3 Cells
chemical_list: D000970:Antineoplastic Agents; D011505:Protein-Tyrosine Kinases