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Dabrafenib

Cat. No. M1988
Dabrafenib Structure
Synonym:

GSK2118436

Size Price Availability Quantity
10mg USD 85 In stock
50mg USD 185 In stock
200mg USD 400 In stock
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Quality Control
Biological Activity

Dabrafenib (GSK2118436A) is a potent ATP-competitive inhibitor of B-Raf, B-Raf V600E and c-Raf with IC50 of 3.2 nM, 0.8 nM and 5.0 nM, respectively. Dabrafenib is selective for Raf kinase, with 400 fold selectivity towards B-Raf over 91% of the other kinases tested. Dabrafenib (orally administrated) inhibits the growth of B-RafV600E mutant melanoma (A375P) and colon cancer (Colo205) human tumor xenografts, growing subcutaneously in immuno-compromised mice. GSK2118436 treatment results in no detectable negative impact on existing systemic immunity or the de novo generation of tumor-specific T cells. Dabrafenib (GSK2118436A) is currently in phase III clinical trial in patients with melanoma.

Protocol
Cell Experiment
Cell lines A375-GFP, 888Mel-MEK1T55delinsRT,SK-MEL-28
Preparation method Dose–response curves were performed as follows: 3,000–6,000 cells were plated per well in a 96-well plate. For each condition, triplicates were plated. The next day, drug was added to the wells. At day 5 of the assay, medium-containing drug was removed and survival was measured by CellTiter-Blue Cell Viability Assay (G8081, Promega).
Concentrations 0, 0.25, 0.5, 1, 2.5, 5 µ M
Incubation time 5 Days
Animal Experiment
Animal models A375 cells infected with pQXCIPGFP, MEK1WT, and MEK1T55delinsRT Mice--Derived Xenografts
Formulation Dabrafenib powder was first dissolved in DMSO and consequently, before injection, dissolved in 0.5% hydroxypropylmethylcellulose (Sigma-Aldrich), 0.2% Tween-80 in pH 8.0 distilled H2O.
Dosages 30 mg/kg daily (6 days per week)
Administration oral gavage
Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)
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 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.

Chemical Information
Molecular Weight 519.56
Formula C23H20F3N5O2S2
CAS Number 1195765-45-7
Purity 100.00%
Solubility DMSO 30 mg/mL
Storage at -20°C
Customer Product Validations & Biological Datas
Source Journal of Cell Science (2016) . Figure 3. Dabrafenib (M1988, Abmole, Houston, TX)
Method Cell apoptosis assay and western blot
Cell Lines IM9 and RPMI8226 cells expressing PAX5
Concentrations 10 μM
Incubation Time 30 h
Results Similarly, the selective RIP2 inhibitor SB 203580, but not the RIP1 inhibitor Necrostatin-1 (Degterev et al., 2013) nor the RIP3 inhibitor Dabrafenib (Li et al., 2014), was able to significantly increase Bortezomib-induced apoptosis in IM9 andPAX5-expressing RPMI8226 cells (Fig. 3D). Furthermore, only SB 203580 decreased Bortezomib-induced activation of RIP2 and NF-κB in IM9 cells (Fig. 3F).
Rating
Source Cell Report (2016). Figure 7.dabrafenib (GSK2118436, Abmole)
Method Tumour volume and Immunoblotting
Cell Lines
Concentrations 30 mg/kg
Incubation Time 25~30 days
Results BRAFV600E/DK is Responsible for Resistance to BRAFi.Both PDXs were treated either with the BRAF inhibitor dabrafenib, to which they were completely resistant (Figures 7G and 7H). Indeed, AKT signaling was much more active in the M048R2.X2 PDX (Figure 7I), explaining its only partial sensitivity to LY3009120.
Rating
Source Cell Report (2016). Figure 3.dabrafenib (GSK2118436, Abmole)
Method Immunoblotting and qPCR
Cell Lines
Concentrations 30 mg/kg
Incubation Time 25~30 days
Results These results demonstrate concordance between drug responses in patients and their corresponding PDXs, and they illustrate that the therapy response can be either stable or dynamic.
Rating
Source Cell Report (2014) . Figure 7.Dabrafenib (Abmole)
Method In Vivo Experiments
Cell Lines M026R.X1 tumors
Concentrations 30mg/kg
Incubation Time 33 days
Results Synthetic lethality by hypoxia induction and Chek1/2 inhibition in vivo was observed for the PDX derived from a melanoma patient who had acquired resistance to BRAF inhibition.
Rating
Source EMBO Molecular Medicine (2015) . Figure 4.Dabrafenib (GSK2118436, Abmole)
Method Mice--Derived Xenografts
Cell Lines A375 cells infected with pQXCIPGFP, MEK1WT, and MEK1T55delinsRT
Concentrations 30 mg/kg daily by oral gavage
Incubation Time 12 days
Results Altogether, these data confirm that MEK1T55delinsRT confers resistance to BRAF inhibition in vivo and induces local invasion.
Rating
Source EMBO Molecular Medicine (2015) . Figure 4.Dabrafenib (GSK2118436, Abmole)
Method CellTiter-Blue Cell Viability Assay (G8081, Promega)
Cell Lines A375-GFP, 888Mel-MEK1T55delinsRT,SK-MEL-28
Concentrations 0, 0.25, 0.5, 1, 2.5, 5 µ M
Incubation Time 5 days
Results MEK1T55delinsRT-expressing cells were also more resistant to low levels of the ERK inhibitor SCH772984 than control populations (Fig 4F and G).
Rating
Product Citations
References

Combinations of BRAF, MEK, and PI3K/mTOR inhibitors overcome acquired resistance to the BRAF inhibitor GSK2118436 dabrafenib, mediated by NRAS or MEK mutations.
Greger JG, et al. Mol Cancer Ther. 2012 Apr;11(4):909-20. PMID: 22389471.

BRAF(V600) inhibitor GSK2118436 targeted inhibition of mutant BRAF in cancer patients does not impair overall immune competency.
Hong DS, et al. Clin Cancer Res. 2012 Apr 15;18(8):2326-35. PMID: 22355009.

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  Catalog
Abmole Inhibitor Catalog 2017




Keywords: Dabrafenib, GSK2118436 supplier, Raf, inhibitors

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