Sorafenib Tosylate 化学構造
分子量: 637.03

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製品説明

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製品の説明

生物活性

製品説明 Sorafenib Tosylateは、Raf-1、B-RafとVEGFR-2のマルチキナーゼ阻害剤で、IC50 がそれぞれ 6 nM、 22 nM、90 nMです。
ターゲット Raf-1 B-Raf VEGFR2 PDGFRβ
IC50 6 nM 22 nM 90 nM 57 nM [1]
In vitro試験 Sorafenib tosylate inhibits both wild-type and V599E mutant B-Raf activity with IC50 of 22 nM and 38 nM, respectively. Sorafenib tosylate also potently inhibits mVEGFR2 (Flk-1), mVEGFR3, mPDGFRβ, Flt3, and c-Kit with IC50 of 15 nM, 20 nM, 57 nM, 58 nM, and 68 nM, respectively. Sorafenib tosylate weakly inhibits FGFR-1 with IC50 of 580 nM. Sorafenib tosylate is not active against ERK-1, MEK-1, EGFR, HER-2, IGFR-1, c-Met, PKB, PKA, cdk1/cyclinB, PKCα, PKCγ, and pim-1. Sorafenib tosylate markedly inhibits VEGFR2 phosphorylation in NIH 3T3 cells with IC50 of 30 nM, and Flt-3 phosphorylation in HEK-293 cells with IC50 of 20 nM. Sorafenib tosylate potently blocks MEK 1/2 and ERK 1/2 phosphorylation in most cell lines but not in A549 or H460 cells, while having no effect on inhibition of the PKB pathway. Sorafenib tosylate inhibits the proliferation of HAoSMC and MDA-MB-231 cells with IC50 of 0.28 μM and 2.6 μM, respectively. [1] In addition to inhibition of the RAF/MEK/ERK signaling pathway, Sorafenib tosylate significantly inhibits the phosphorylation of eIF4E and down-regulates Mcl-1 levels in hepatocellular carcinoma (HCC) cells in a MEK/ERK-independent manner. Sorafenib tosylate inhibits the proliferation of PLC/PRF/5 and HepG2 cells with IC50 of 6.3 μM and 4.5 μM, respectively, and leads to the significant induction of apoptosis. [2]
Cell Data
Cell LinesAssay TypeConcentrationIncubation TimeFormulationActivity DescriptionPMID
MDA-MB-435 NGG2e3dIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NWLtcGxMPDhiaB?= NE\5OplIUTVyPUKg{txO M1XaPVIzPTZyNkK3
UACC257 MXLHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MXy0PEBp MVfHTVUxRTJizszN MlH3NlI2PjB4Mke=
MCF7 MXjHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NF;tcmc1QCCq MlHHS2k2OD1{LkWg{txO NHjSUmQzOjV4ME[yOy=>
EKVX MX\Hdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MYO0PEBp M4TCdWdKPTB;Mj61JO69VQ>? MkPmNlI2PjB4Mke=
HT-29 M1qxcGdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NUXEW3hCPDhiaB?= MVnHTVUxRTJwNTFOwG0> NH\XOJYzOjV4ME[yOy=>
SNB19 MYnHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NFrrdG81QCCq MnfaS2k2OD1|LkKg{txO NF;tNYEzOjV4ME[yOy=>
OVCAR3 NGPjOoxIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NUTISoRUPDhiaB?= M2fyZWdKPTB;Mz6yJO69VQ>? NGXkbXkzOjV4ME[yOy=>
CAKI-1 Ml3US5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NEfvRlQ1QCCq MUfHTVUxRTNwMjFOwG0> M3n3NFIzPTZyNkK3
SW620 MmD1S5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NVfvPFlkPDhiaB?= NF:zc4JIUTVyPUOuNkDPxE1? NXjsPXhjOjJ3NkC2Nlc>
TK10 M1e1NGdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 M2nlSVQ5KGh? NXPQSXlsT0l3ME21JO69VQ>? NI\VNYkzOjV4ME[yOy=>

... Click to View More Cell Line Experimental Data

In vivo試験 Oral administration of Sorafenib tosylate (~60 mg/kg) demonstrates broad spectrum, dose-dependent anti-tumor activity against a variety of human tumor xenograft models including MDA-MB-231, Colo-205, HT-29, DLD-1, NCI-H460, and A549, with no evidence of toxicity. In association with the anti-tumor efficacy, Sorafenib tosylatetreatment potently inhibits MEK 1/2 phosphorylation and pERK 1/2 levels in HT-29 and MDA-MB-231 xenografts but not in Colo-205 xenografts, and significantly suppresses tumor microvessel area (MVA) and microvessel density (MVD) in MDA MB-231, HT-29 and Colo-205 tumor xenografts. [1] Sorafenib tosylate treatment produces dose-dependent growth inhibition of PLC/PRF/5 tumor xenografts in SCID mice with TGIs of 49% and 78% at 10 mg/kg and 30 mg/kg, respectively, consistent with the inhibition of ERK and eIF4E phosphorylation, reduction of the microvessel area, and induction of tumor cell apoptosis. [2]
臨床試験 Sorafenib sensitizes bax-/- cells to TRAIL in a dose-dependent manner, through a mechanism involving down-regulating NF-κB mediated Mcl-1 and cIAP2 expression. Combining Sorafenib (30-60 mg/kg) with TRAIL (5 mg/kg) show dramatic efficacy in TRA
特集

プロトコル (参考用のみ)

キナーゼアッセイ: [1]

Biochemical assays Recombinant baculoviruses expressing Raf-1 (residues 305–648) and B-Raf (residues 409–765) are purified as fusion proteins. Full-length human MEK-1 is generated by PCR and purified as a fusion protein from Escherichia coli lysates. Sorafenib tosylate is added to a mixture of Raf-1 (80 ng), or B-Raf (80 ng) with MEK-1 (1 μg) in assay buffer [20 mM Tris (pH 8.2), 100 mM NaCl, 5 mM MgCl2, and 0.15% β-mercaptoethanol] at a final concentration of 1% DMSO. The Raf kinase assay (final volume of 50 μL) is initiated by adding 25 μL of 10 μM γ[33P]ATP (400 Ci/mol) and incubated at 32 °C for 25 minutes. Phosphorylated MEK-1 is harvested by filtration onto a phosphocellulose mat, and 1% phosphoric acid is used to wash away unbound radioactivity. After drying by microwave heating, a β-plate counter is used to quantify filter-bound radioactivity. Human VEGFR2 (KDR) kinase domain is expressed and purified from Sf9 lysates. Time-resolved fluorescence energy transfer assays for VEGFR2 are performed in 96-well opaque plates in the time-resolved fluorescence energy transfer format. Final reaction conditions are as follows: 1 to 10 μM ATP, 25 nM poly GT-biotin, 2 nM Europium-labeled phospho (p)-Tyr antibody (PY20), 10 nM APC, 1 to 7 nM cytoplasmic kinase domain in final concentrations of 1% DMSO, 50 mM HEPES (pH 7.5), 10 mM MgCl2, 0.1 mM EDTA, 0.015% Brij-35, 0.1 mg/mL BSA, and 0.1% β-mercaptoethanol. Reaction volumes are 100 μL and are initiated by addition of enzyme. Plates are read at both 615 and 665 nM on a Perkin-Elmer VictorV Multilabel counter at ~1.5 to 2.0 hours after reaction initiation. Signal is calculated as a ratio: (665 nm/615 nM) × 10,000 for each well. For IC50 generation, Sorafenib tosylate is added before the enzyme initiation. A 50-fold stock plate is made with Sorafenib tosylate serially diluted 1:3 in a 50% DMSO/50% distilled water solution. Final Sorafenib tosylate concentrations range from 10 μM to 4.56 nM in 1% DMSO.

細胞アッセイ: [1]

細胞株 MDA-MB-231, and HAoSMC
濃度 Dissolved in DMSO, final concentrations ~10 μM
反応時間 72 hours
実験の流れ Cells are exposed to increasing concentrations of Sorafenib tosylate for 72 hours. Cell number is quantitated using the Cell TiterGlo ATP Luminescent assay kit. This assay measures the number of viable cells per well by measurement of luminescent signal based on amount of cellular ATP.

動物実験: [1]

動物モデル Female NCr-nu/nu mice implanted s.c. with MDA-MB-231, Colo-205, HT-29, H460, or A549 cells
製剤 Dissolved in Cremophor EL/ethanol (50:50) as 4-fold (4 × stock solution, and diluted to 1 × with w
投薬量 ~60 mg/kg
投与方法 Orally once daily

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

SpeciesMouseRatRabbitGuinea pigHamsterDogMonkeyBaboon
Weight (kg)0.020.151.80.40.0810312
Body Surface Area (m2)0.0070.0250.150.050.020.50.240.6
Km factor361285201220
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.

Rat dose (mg/kg) = mouse dose (22.4 mg/kg) ×  mouse Km(3)  = 11.2 mg/kg
rat Km(6)
1

参考

化学情報

Download Sorafenib Tosylate SDF
分子量 637.03
化学式

C21H16ClF3N4O3.C7H8O3S

CAS No. 475207-59-1
保管 2年-20℃
6月-80℃in solvent
別名 Bay 43-9006
溶解度 (25°C) * In vitro DMSO 127 mg/mL (199.36 mM)
0.01 mg/mL (0.01 mM)
エタノール <1 mg/mL (<1 mM)
In vivo 2% Cremophor EL, 2% N,N-dimethylacetamide 30 mg/mL
* <1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.
化学名 2-Pyridinecarboxamide, 4-[4-[[[[4-chloro-3-(trifluoromethyl)phenyl]amino]carbonyl]amino]phenoxy]-N-methyl-, 4-methylbenzenesulfonate (1:1)

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
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