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Purity: ≥98%
MLN2480 (BIIB-024; BSK1369; DAY-101; TAK-580; AMG-2112819) is an orally bioactive, potent and selective pan-Raf kinase inhibitor with potential anticancer activity. It is being tested clinically on people with advanced solid tumors or melanoma. At concentrations that are tolerated in vivo, MLN2480 inhibits MAPK pathway signaling in some RAS mutant and BRAF mutant preclinical cancer models. At very low concentrations, it is found to activate phosphorylated MEK, but at higher concentrations, it inhibits this same activity. Different models and genetic contexts are found to have different MLN-2480 inhibitory effects. The Raf kinases (A-Raf, B-Raf, and C-Raf) are important mediators of the mitogen-activated protein kinase (MAPK) pathway, which controls cell growth and survival. In many cases, Ras or Raf activating mutations lead to the MAPK pathway becoming dysregulated in human cancers.
| Targets |
Raf
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|---|---|
| ln Vitro |
MLN2480 inhibits MAPK pathway signaling at concentrations that are tolerated in vivo in BRAF mutant and some RAS mutant preclinical cancer models[1].
At very low concentrations, it is found to activate phosphorylated MEK, whereas at higher concentrations, it inhibits this same activity. It has been discovered that MLN-2480's inhibitory effects differ between models and genetic contexts[2]. In vitro testing of the drug combination of MLN2480 and TAK-733 (an investigational allosteric MEK kinase inhibitor) in cell proliferation assays shows synergistic activity. Additionally, western blot analysis shows how MLN2480 reverses the feedback activation of MEK in response to TAK-733, resulting in more concerted MAPK pathway inhibition. PRAK is only weakly inhibited by MLN-2480 [1][2]. |
| ln Vivo |
MLN2480 exhibits antitumor activity in vivo in xenograft models for pancreatic, lung, colon, and melanoma cancer[3].
MLN-2480 (37.5 mg/kg) in a tumor xenograft model is tolerable. An SK-MEL-30 xenograft model benefits from the combination of MLN-2480 (12.5 mg) and TAK-733 (1 mg/kg), but neither drug by itself has much of an impact[2]. |
| Enzyme Assay |
MLN2480 (also known as BIIB-024, TAK-580 and AMG 2112819) is an orally bioactive, potent and selective pan-Raf kinase inhibitor that is under in clinical investigation. At concentrations that are tolerated in vivo, MLN2480 inhibits MAPK pathway signaling in some RAS mutant and BRAF mutant preclinical cancer models.
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| Cell Assay |
In vitro, MLN-2480 is effective against both wild-type and B-raf Val600Glu. At very low concentrations, MLN-2480 is found to activate phosphorylated MEK, but at higher concentrations, it inhibits this same activity. High concentrations of MLN-2480 block the signaling pathway in the human malignant melanoma A-375 mutant B-raf Val600Glu cell line. MLN-2480's inhibitory effects are found to vary depending on the model and genetic context; it only mildly inhibits PRAK. High levels of apoptotic biomarkers were seen when MLN-2480 and TAK-733 were combined in NRAS mutant human malignant melanoma cell lines (SK-MEL-2).
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| Animal Protocol |
C57BL/6J mice
12.5 mg/kg oral gavage |
| References |
| Molecular Formula |
C17H12CL2F3N7O2S
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|---|---|---|
| Molecular Weight |
506.29
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| Exact Mass |
505.01
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| Elemental Analysis |
C, 40.33; H, 2.39; Cl, 14.01; F, 11.26; N, 19.37; O, 6.32; S, 6.33
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| CAS # |
1096708-71-2
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| Related CAS # |
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| Appearance |
Solid powder
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| SMILES |
C[C@H](C1=NC=C(S1)C(=O)NC2=NC=C(C(=C2)C(F)(F)F)Cl)NC(=O)C3=C(C(=NC=N3)N)Cl
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| InChi Key |
VWMJHAFYPMOMGF-ZCFIWIBFSA-N
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| InChi Code |
InChI=1S/C17H12Cl2F3N7O2S/c1-6(28-15(31)12-11(19)13(23)27-5-26-12)16-25-4-9(32-16)14(30)29-10-2-7(17(20,21)22)8(18)3-24-10/h2-6H,1H3,(H,28,31)(H2,23,26,27)(H,24,29,30)/t6-/m1/s1
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| Chemical Name |
2-[(1R)-1-[(6-amino-5-chloropyrimidine-4-carbonyl)amino]ethyl]-N-[5-chloro-4-(trifluoromethyl)pyridin-2-yl]-1,3-thiazole-5-carboxamide
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| Synonyms |
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| HS Tariff Code |
2934.99.9001
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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: ≥ 0.67 mg/mL (1.32 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 6.7 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: ≥ 0.67 mg/mL (1.32 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 6.7 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: ≥ 0.67 mg/mL (1.32 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.9752 mL | 9.8758 mL | 19.7515 mL | |
| 5 mM | 0.3950 mL | 1.9752 mL | 3.9503 mL | |
| 10 mM | 0.1975 mL | 0.9876 mL | 1.9752 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.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT01425008 | Completed | Drug: MLN2480 | Melanoma Solid Tumor |
Millennium Pharmaceuticals, Inc. |
September 15, 2011 | Phase 1 |
| NCT02327169 | Completed | Drug: MLN2480 Drug: MLN0128 |
Advanced Nonhematologic Malignancies |
Millennium Pharmaceuticals, Inc. |
January 14, 2015 | Phase 1 |
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