BAY 43-9006 Exhibits Broad Spectrum Oral Antitumor Activity and Targets the RAF/MEK/ERK Pathway and Receptor Tyrosine Kinases Involved in Tumor Progression and Angiogenesis

摘要: The RAS/RAF signaling pathway is an important mediator of tumor cell proliferation and angiogenesis. novel bi-aryl urea BAY 43-9006 a potent inhibitor Raf-1, member the RAF/MEK/ERK pathway. Additional characterization showed that suppresses both wild-type V599E mutant BRAF activity in vitro. In addition, demonstrated significant against several receptor tyrosine kinases involved neovascularization progression, including vascular endothelial growth factor (VEGFR)-2, VEGFR-3, platelet-derived beta, Flt-3, c-KIT. cellular mechanistic assays, inhibition mitogen-activated protein kinase colon, pancreatic, breast lines expressing KRAS or BRAF, whereas non-small-cell lung cancer were insensitive to by 43-9006. Potent VEGFR-2, VEGFR-3 autophosphorylation was also observed for Once daily oral dosing broad-spectrum antitumor breast, xenograft models. Immunohistochemistry close association between extracellular signal-regulated (ERKs) 1/2 phosphorylation two three models examined, consistent with some but not all analyses microvessel density area same sections using antimurine CD31 antibodies These data demonstrate dual action RAF VEGFR targets