Sorafenib (D3)

Sorafenib-d₃ is intended for use as an internal standard for the quantification of sorafenib by GC- or LC-MS. Sorafenib is a multi-kinase inhibitor that inhibits Raf-1 and B-RAF (IC₅₀s = 6 and 22 ?M, respectively), as well as the receptor tyrosine kinases VEGFR2, VEGFR3, PDGFRβ, FLT3, and c-Kit (IC₅₀s = 90, 15, 20, 57, and 58 nM, respectively).^1,2 It is selective for these kinases over 12 other kinases, including ERK1, MEK1, EGFR, and HER2 (IC₅₀s = >10 ?M for all).² Sorafenib inhibits proliferation of PLC/PRF/5 and HepG2 cells (IC₅₀s = 6.3 and 4.5 ?M, respectively) and induces apoptosis in these cells.³ It completely inhibits tumor growth in a PLC/PRF/5 mouse xenograft model when administered at a dose of 30 mg/kg and reduces basic FGF-induced angiogenesis in a Matrigel^? assay in vivo.^3,4 Sorafenib (10 ?M) induces ferroptotic cell death in HT-1080 fibrosarcoma cells, an effect that can be blocked by the ferroptosis inhibitors ferrostatin-1 , deferoxamine , and β-mercaptoethanol.⁵ It inhibits glutamate release by the system x_c^- cystine/glutamate transporter in HT-1080 cells when used at concentrations ranging from 2.5 to 10 ?M, decreases glutathione levels, and increases lipid peroxidation. Sorafenib also inhibits replication of hepatitis C virus (HCV) in Huh7.5 cells (IC₅₀ = 7.2 ?M).⁶ Formulations containing sorafenib have been used in the treatment of hepatocellular, renal cell, and thyroid carcinomas.

1.Lyons, J.F., Wilhelm, S., Hibner, B., et al.Discovery of a novel Raf kinase inhibitorEndocr. Relat. Cancer8(3)219-225(2001) 2.Wilhelm, S.M., Carter, C., and Tang, L.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 angiogenesisCancer Res.64(19)7099-7109(2004) 3.Liu, L., Cao, Y., Chen, C., et al.Sorafenib blocks the RAF/MEK/ERK pathway, inhibits tumor angiogenesis, and induces tumor cell apoptosis in hepatocellular carcinoma model PLC/PRF/5Cancer Res.66(24)11851-11858(2006) 4.Murphy, D.A., Makonnen, S., Lassoued, W., et al.Inhibition of tumor endothelial ERK activation, angiogenesis, and tumor growth by sorafenib (BAY43-9006)Am. J. Pathol.169(5)1875-1885(2006) 5.Dixon, S.J., Patel, D.N., Welsch, M., et al.Pharmacological inhibition of cystine-glutamate exchange induces endoplasmic reticulum stress and ferroptosisElife3e02523(2014) 6.Himmelsbach, K., Sauter, D., Baumert, T.F., et al.New aspects of an anti-tumour drug: Sorafenib efficiently inhibits HCV replicationGut58(12)1644-1653(2009)