Sorafenib (BAY 43-9006) is a dual-action inhibitor that targets RAF/MEK/ERK pathway in tumor cells and tyrosine kinases VEGFR/PDGFR in tumor vasculature. A novel class of biaryl urea that inhibits C-RAF kinase was discovered using a combination of medicinal and combinatorial chemistry approaches. This effort culminated in the identification of the clinical candidate BAY 43-9006 (Sorafenib). Sorafenib inhibited the kinase activity of both C-RAF and B-RAF (wild type and V600E mutant). It inhibited MEK and ERK phosphorylation in various cancer cell lines and tumor xenografts and exhibited potent oral antitumor activity in a broad spectrum of human tumor xenograft models. Further characterization of sorafenib revealed that this molecule was a multikinase inhibitor that targeted the vascular endothelial growth factor receptor family (VEGFR-2 and VEGFR-3) and platelet-derived growth factor receptor family (PDGFR-beta and Kit), which play key roles in tumor progression and angiogenesis.
|Cell lines||MDA-MB-231, Mia PaCa 2, HCT 116, LOX melanoma and pancreatic BxPC-3, NCI-H460 and A549 cell lines|
|Preparation method||Tumor Cell Proliferation.
Tumor cells were trypsinized and plated in 96-well plates at 3000 cells per well in complete media with 10% FCS. Cells were incubated overnight at 37°C, and the next day, compounds were added in complete growth media over a final concentration range of 10 μmol/L to 10 nmol/L in 0.1% DMSO. Cells were incubated with test compounds for 72 hours at 37°C in complete growth media, and cell number was quantitated using the Cell TiterGlo ATP Luminescent assay kit (Promega). This assay measures the number of viable cells per well by measurement of luminescent signal based on amount of cellular ATP.
|Concentrations||10 μmol/L to 10 nmol/L|
|Incubation time||72 h|
|Animal models||MDA-MB-231, Colo-205, HT-29, DLD-1, NCI-H460, and A549 tumors xenograft model in Female NCr-nu/nu mice|
|Formulation||Cremophor EL/ethanol (50:50; Sigma Cremophor EL, 95% ethyl alcohol)|
|Dosages||7.5, 15, 30 and 60 mg/kg, qd×9|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
|Solubility||DMSO ≥100 mg/mL|
|Source||Drug Metab Dispos (2010). Figure 2. Sorafenib Tosylate|
|Cell Lines||Male FVB Tac-(KO)mdr1a-(KO)Mdr1b mice|
|Results||Distribution of radioactivity into the brain was also investigated 1 and 4 h after oral administration of 0.5 and 4 mg/kg [14C]sorafenib tosylate. Plasma concentrations were not affected by the knockout of P-gp|
|Source||Drug Metab Dispos (2010). Figure 1. Sorafenib Tosylate|
|Cell Lines||Male FVB Tac-(KO)mdr1a-(KO)Mdr1b mice|
|Concentrations||0.5 and 4 mg/kg|
|Incubation Time||8 weeks|
|Results||Whole brain concentrations in mdr1a/1b(-/-) mice 1 h after intravenous administration of 0.5 mg/kg [14C]sorafenib tosylate were statistically higher (p < 0.05) and showed a tendency toward higher concentrations at the other time points investigated compared with those in the WT mice|
A double-blind, randomised, placebo-controlled, phase 2b study evaluating sorafenib in combination with paclitaxel as a first-line therapy in patients with HER2-negative advanced breast cancer.
Gradishar et al. Eur J Cancer. 2012 Sep 3. PMID: 22954665.
Sorafenib has potent anti-tumor activity in multiple myeloma in vitro, ex vivo and in vivo, in the 5T33MM mouse model.
Kharaziha et al. Cancer Res. 2012 Sep 4. PMID: 22952216.
The important roles of RET, VEGFR2 and the RAF/MEK/ERK pathway in cancer treatment with sorafenib.
Mao et al. Acta Pharmacol Sin. 2012 Sep 3. PMID: 22941289.
Differential inhibitory effects of two Raf-targeting drugs, sorafenib and PLX4720, on the growth of multidrug-resistant cells.
Eum et al. Mol Cell Biochem. 2012 Sep 2. PMID: 22941213.
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.
Wilhelm SM, et al. Cancer Res. 2004 Oct 1;64(19):7099-109. PMID: 15466206.
|Related VEGFR/PDGFR Products|
Avapritinib (BLU-285) is a small molecule kinase inhibitor that potently inhibits PDGFRα D842V mutant activity in vitro (IC50 = 0.5 nM) and PDGFRα D842V autophosphorylation in the cellular setting (IC50 = 30 nM); also a potent inhibitor of the analogous KIT mutation, D816V in KIT Exon 17 (IC50 = 0.5 nM).
|Nintedanib Ethanesulfonate Salt
BIBF 1120 esylate is a potent triple angiokinase inhibitor for VEGFR1/2/3, FGFR1/2/3 and PDGFRα/β with IC50s of 34 nM/13 nM/13 nM, 69 nM/37 nM/108 nM and 59 nM/65 nM, respectively.
Regorafenib (BAY 73-4506) is a multi-target inhibitor for VEGFR1, VEGFR2, VEGFR3, PDGFRβ, Kit, RET and Raf-1 with IC50 of 13 nM/4.2 nM/46 nM, 22 nM, 7 nM, 1.5 nM and 2.5 nM, respectively.
|Pazopanib HCl (GW786034 )
Pazopanib HCl (GW786034 HCl) is a novel multi-target inhibitor of VEGFR1, VEGFR2, VEGFR3, PDGFR, FGFR, c-Kit and c-Fms with IC50 of 10 nM, 30 nM, 47 nM, 84 nM, 74 nM, 140 nM and 146 nM in cell-free assays, respectively.
|Dovitinib (TKI-258) Dilactic Acid
Dovitinib Dilactic acid (TKI258 Dilactic acid) is the Dilactic acid of Dovitinib, which is a multitargeted RTK inhibitor, mostly for class III (FLT3/c-Kit) with IC50 of 1 nM/2 nM.
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