Preclinical evaluation of a novel orally available SRC/Raf/VEGFR2 inhibitor, SKLB646, in the treatment of triple negative breast cancer

Zheng, M.W., Zhang, C.H., Chen, K., Huang, M., Li, Y.P., Lin, W.T., Zhang, R.J., Zhong, L., Xiang, R., Li, L.L., Liu, X.Y., Wei, Y.Q., Yang, S.Y.
Molecular cancer therapeutics   15(3): 366-78 (Journal)
Registered Authors
Chen, Kai, Huang, Mei
MeSH Terms
  • Angiogenesis Inhibitors/pharmacology
  • Animals
  • Animals, Genetically Modified
  • Antineoplastic Agents/pharmacology*
  • Apoptosis/drug effects
  • Biomarkers, Tumor
  • Cell Cycle/drug effects
  • Cell Line, Tumor
  • Cell Movement/drug effects
  • Cell Proliferation/drug effects
  • Cell Survival/drug effects
  • Disease Models, Animal
  • Enzyme Activation/drug effects
  • Female
  • Humans
  • Inhibitory Concentration 50
  • Neoplasm Metastasis
  • Protein Kinase Inhibitors/pharmacology*
  • Proto-Oncogene Proteins B-raf/antagonists & inhibitors*
  • Signal Transduction/drug effects
  • Triple Negative Breast Neoplasms/drug therapy
  • Triple Negative Breast Neoplasms/metabolism*
  • Triple Negative Breast Neoplasms/mortality
  • Triple Negative Breast Neoplasms/pathology
  • Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors*
  • Xenograft Model Antitumor Assays
  • Zebrafish
  • src-Family Kinases/antagonists & inhibitors*
26721945 Full text @ Mol. Cancer Ther.
Triple-negative breast cancer (TNBC) is the most aggressive and deadly breast cancer subtype. To date, chemotherapy is the only systemic therapy and prognosis remains poor. Herein, we report the preclinical evaluation of SKLB646 in the treatment of TNBC; SKLB646 is a novel multiple kinase inhibitor developed by us recently. This compound potently inhibited SRC and VEGFR2 with IC50 values of 0.002 μM and 0.012 μM, respectively. It also considerably inhibited B-Raf and C-Raf with IC50 values of 0.022 and 0.019 μM, respectively. It exhibited significant anti-proliferation and anti-viability activities against TNBC cell lines. Studies of mechanism of action indicated that SKLB646 inhibited the activation of SRC signaling and blocked the MAPK signaling through inhibiting the Raf kinases. Interestingly, SKLB646 dose-dependently down-regulated the expression of Fra1, a transcriptional factor that plays a critical role in the epithelial-to-mesenchymal transition. Additionally, SKLB646 could inhibit HUVEC proliferation, migration and invasion. It effectively blocked the formation of intersegmental vessels in zebrafish embryos and displayed considerable antiangiogenic effects in the tumor-induced neovascularization zebrafish model. In TNBC xenograft models, SKLB646 suppressed the tumor growth in a dose-dependent manner. Moreover, SKLB646 could remarkably inhibit TNBC cell migration and invasion in vitro. Further, in an experimental lung metastasis model, the overall survival time of groups treated with SKLB646 was much lengthened compared with the control, dasatinib and paclitaxel treated groups. In a preliminary pharmacokinetic study, SKLB646 showed good pharmacokinetic properties. Taken together, the preclinical data show that SKLB646 could be a promising lead compound for the treatment of TNBC.
Genes / Markers
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Engineered Foreign Genes