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Purity: ≥98%
SB590885 (SB 590885; SB-590885) is a novel and potent B-Raf inhibitor with potential antineoplastic activity. With a Ki of 0.16 nM in a cell-free assay, it inhibits B-Raf and shows an 11-fold preference for B-Raf over c-Raf. It doesn't block kinases that are related to each other closely. In order to stabilize B-Raf'sactiveconformation, it is discovered that SB590885 binds to B-Raf inside the ATP-binding pocket. Only tumor cells expressing oncogenic B-Raf V600E are inhibited by SB590885's ability to phosphorylate ERK and show anti-proliferation. When exposed to SB-590885, cancer cell lines and normal cells exhibit varying sensitivity to or resistance to the treatment, whereas malignant cells expressing oncogenic B-Raf exhibit selective inhibition of mitogen-activated protein kinase activation, proliferation, transformation, and tumorigenicity.
| Targets |
B-Raf (Ki = 0.16 nM); c-Raf (Ki = 1.72 nM)
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| ln Vitro |
SB590885 displays significant selectivity for B-Raf over c-Raf with Ki of 0.16 nM over 1.72 nM. The previously described Raf/VEGFR kinase inhibitor BAY 439006 (Ki = 38 nM for mutant B-Raf, 6 nM for c-Raf) is not as effective as SB-590885 as an inhibitor. Over 46 different kinases, SB590885 exhibits strong selectivity. The multi-kinase inhibitor BAY43-9006 does not stabilize the oncogenic B-Raf kinase domain in an active state, as does SB590885. SB590885 treatment potently inhibits ERK phosphorylation with EC50 values of 28 nM, 58 nM, 290 nM, 58 nM, and 190 nM, respectively, in Colo205, HT29, A375P, SKMEL28, and MALME-3M cells expressing oncogenic B-RafV600E. It also consistently inhibits proliferation with EC50 values of 0.1 μM, 0.87 μM, 0.37 μM, 0.12 μM, and 0.15 μM. SB590885 selectively inhibits the anchorage-independent growth of melanoma cell lines. [1] With a Kd of 0.3 nM, SB590885 exhibits high affinity for B-Raf. [2] The majority of melanoma cell lines (451Lu, WM35, and WM983) with the BRAF V600E mutation and no CDK4 mutations are very sensitive to SB590885, with an IC50 of <1 μM. In B-Raf V600E-mutated melanomas, elevated cyclin D1 levels brought on by genomic amplification are responsible for the drug's resistance. [3]
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| ln Vivo |
In murine xenografts created from mutant B-Raf-expressing A375P melanoma cells, SB-590885 administration significantly and modestly inhibits tumor growth[1].
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| Enzyme Assay |
SB-590885 is a potent B-Raf inhibitor with Ki of 0.16 nM, and has 11-fold greater selectivity for B-Raf over c-Raf, without inhibition to other human kinases.
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| Cell Assay |
For the proliferation tests, cells are treated with substances in 0.1% DMSO and incubated for 72 hours at 37°C with 5% CO2. A Victor 2V plate reader and the CellTiter-Glo reagent are used to measure the number of viable cells. According to the directions provided by the manufacturer, cells are prepared for cell cycle analysis on a Becton Dickinson FACScan. Using the software CellQuest v3.3, data is gathered and examined. Using inhibitors or DMSO vehicle in the agar layer, anchorage-independent growth assays are carried out as previously described. For a total of 28 days, cultures are fed again with media, an inhibitor, or DMSO every 5 to 7 days. Utilizing standard light microscopy, colonies are viewed, captured on camera, and quantified by triplicate counting on a grid.
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| Animal Protocol |
Following i.p. injection, the pharmacokinetic characteristics and safety of SB-590885 were assessed. It was discovered that daily injections of 50 mg/kg resulted in therapeutic levels with only minor changes in body weight. 8 to 12-week-old female nude mice are used to create the tumors. Tumors are induced by injecting 5×106 A375P cells in Matrigel suspension intravenously. Three weeks later, when the tumors have reached a volume of 150 to 250 mm3, the mice are randomized into groups of eight and then given the appropriate treatment. Animals are administered either the vehicle (2% N,N-dimethylacetamide, 2% Cremophor EL, and 96% acidified water (pH 4-5)) or the vehicle (daily for 21 days) containing 50 mg/kg of SB-590885. Then, 14 days after the end of the treatment, a cohort of mice that had been given SB-590885 are observed once more. Two times per week, calipers are used to measure the tumor volume for 55 days.
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| References |
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| Molecular Formula |
C27H27N5O2
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| Molecular Weight |
453.54
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| Exact Mass |
453.21647512
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| CAS # |
405554-55-4
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| Related CAS # |
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| Appearance |
Solid
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| SMILES |
CN(C)CCOC1=CC=C(C=C1)C2=NC(=C(N2)C3=CC=NC=C3)C4=CC5=C(C=C4)/C(=N/O)/CC5
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| InChi Key |
MLSAQOINCGAULQ-QFMPWRQOSA-N
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| InChi Code |
InChI=1S/C27H27N5O2/c1-32(2)15-16-34-22-7-3-19(4-8-22)27-29-25(18-11-13-28-14-12-18)26(30-27)21-5-9-23-20(17-21)6-10-24(23)31-33/h3-5,7-9,11-14,17,33H,6,10,15-16H2,1-2H3,(H,29,30)/b31-24+
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| Chemical Name |
(NE)-N-[5-[2-[4-[2-(dimethylamino)ethoxy]phenyl]-5-pyridin-4-yl-1H-imidazol-4-yl]-2,3-dihydroinden-1-ylidene]hydroxylamine
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| Synonyms |
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.51 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (5.51 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (5.51 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. Solubility in Formulation 4: 2% Cremophor EL, 2% N,N-dimethylacetamide, pH 5.0: 30mg/mL |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.2049 mL | 11.0244 mL | 22.0488 mL | |
| 5 mM | 0.4410 mL | 2.2049 mL | 4.4098 mL | |
| 10 mM | 0.2205 mL | 1.1024 mL | 2.2049 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
Overexpression of cyclin D1 reduces sensitivity to the BRAF inhibitor SB590885.Mol Cancer Ther.2008 Sep;7(9):2876-83. |
Identification of human melanoma samples and a cell line with high levels of cyclin D1 (CCND1) amplification.A, DNA copy number profiles of chromosome 11 for melanoma tumor samples TB2668F1, TB2673F1, and the melanoma cell line WM39.Mol Cancer Ther.2008 Sep;7(9):2876-83. |
Melanoma cell lines withCDK4mutations are not resistant to SB590885.A, melanoma cell lines with aCDK4mutation (WM39, WM46, SK-Mel-28, WM902B, WM793, and1205Lu: red, open symbols) and melanoma lines withoutCDK4mutations (WM983, WM164, and451Lu; blue, closed symbols) were treated with increasing concentrations of SB590885 (1 nmol/L – 10 μmol/L) for 72 h before being treated with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide.Mol Cancer Ther.2008 Sep;7(9):2876-83. |
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