Sorafenib (BAY 43-9006) Tosylate 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.
J Nanobiotechnology. 2022 Nov 16;20(1):481.
Bone marrow-targetable Green Tea Catechin-Based Micellar Nanocomplex for synergistic therapy of Acute myeloid leukemia
Sorafenib Tosylate purchased from AbMole
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Analysis of the expression, function and signaling of glycogen phosphorylase isoforms in hepatocellular carcinoma
Sorafenib Tosylate purchased from AbMole
J Virol. 2020 Feb 14;94(5):e01791-19.
Targeting Kaposi's Sarcoma-Associated Herpesvirus ORF21 Tyrosine Kinase and Viral Lytic Reactivation by Tyrosine Kinase Inhibitors Approved for Clinical Use
Sorafenib Tosylate purchased from AbMole
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Source | Drug Metab Dispos (2010). Figure 2. Sorafenib Tosylate |
| Method | gastric gavage | |
| Cell Lines | Male FVB Tac-(KO)mdr1a-(KO)Mdr1b mice | |
| Concentrations | 5 ml/kg | |
| Incubation Time | ||
| 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 |
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Source | Drug Metab Dispos (2010). Figure 1. Sorafenib Tosylate |
| Method | oral administration | |
| 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 |
| Cell Experiment | |
|---|---|
| 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 Experiment | |
|---|---|
| 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 |
| Administration | orally |
| Molecular Weight | 637.03 |
| Formula | C21H16ClF3N4O3.C7H8O3S |
| CAS Number | 475207-59-1 |
| Solubility (25°C) | DMSO 30 mg/mL |
| Storage |
Powder -20°C 3 years ; 4°C 2 years In solvent -80°C 6 months ; -20°C 1 month |
| Species | Mouse | Rat | Rabbit | Guinea pig | Hamster | Dog |
| Weight (kg) | 0.02 | 0.15 | 1.8 | 0.4 | 0.08 | 10 |
| Body Surface Area (m2) | 0.007 | 0.025 | 0.15 | 0.05 | 0.02 | 0.5 |
| Km factor | 3 | 6 | 12 | 8 | 5 | 20 |
| Animal A (mg/kg) = Animal B (mg/kg) multiplied by | Animal B Km |
| Animal A Km |
For example, to modify the dose of Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 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 Compound A of 10 mg/kg.
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