| Size | Price | Stock | Qty |
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| 5mg |
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| 10mg |
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| 25mg |
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| 50mg |
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| 100mg |
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Purity: ≥98%
Refametinib (formerly RDEA-119, BAY 86-9766) is an orally bioavailable, highly selective, non-ATP-competitive (allosteric) inhibitor of MEK1/2 that may have antitumor effects. With IC50s of 19 nM and 47 nM, it inhibits MEK1/2. It has excellent in vitro anti-proliferative activity against cancer cell lines containing the V600E BRAF mutant, with GI50 values ranging from 67 nM to 89 nM. In addition, Refametinib showed strong in vivo antitumor activity in the human melanoma A375 tumor xenograft model and clearly inhibited tumor growth.
| Targets |
MEK1 (IC50 = 19 nM); MEK2 (IC50 = 47 nM)
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| ln Vitro |
RDEA119 is highly effective at inhibiting cell proliferation in a number of tumor cell lines, including A375, SK-MEI-28, Colo205, HT-29, and BxPC3. It is specifically bound directly to an allosteric pocket in the MEK1/2 enzymes. RDEA119 has a GI50 range of 67 to 89 nM and inhibits the anchorage-dependent growth of human cancer cell lines containing the gain-of-function V600E BRAF mutant. All cell lines examined have similar GI50 values (40–84 nM) under anchorage-independent conditions. The tissue selectivity of RDEA119 reduces the likelihood of adverse effects on the central nervous system.[1] RDEA119 has no effect on the other 4 cell lines that carried wild-type BRAF, but it significantly reduces the proliferation of the 4 cell lines that carried the BRAF mutation (IC50 of 0.034-0.217 μM vs. 1.413-34.120 μM). Combining RDEA119 with the mTOR inhibitor, temsirolimus, increases the inhibitory effect of RDEA119 in certain cell lines, including OCUT1 (BRAF V600E(+), PIK3CA H1047R(+)), and SW1376 (BRAF V600E(+)). Additionally, RDEA119 and temsirolimus exhibit synergistic effects on the selectively tested OCUT1 and KAT18 cells' autophagic death. [2]
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| ln Vivo |
In the human melanoma A375 tumor model, oral administration of RDEA119 at 50 mg/kg on a once daily × 14 schedule results in a 68% tumor growth inhibition (TGI). In the human colon carcinoma Colo205 tumor model, oral administration of RDEA119 at 25 mg/kg on a once-daily-for-14-days schedule causes a 123% TGI (TGI > 100% occurs when the tumor shrinks below its starting volume). For HT-29 and A431 tumors, a dose of 25 mg/kg given once daily results in TGI of 56% and 67%, respectively. [1]
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| Enzyme Assay |
Escherichia coli expressed with the pET21a vector produces kinase-inactive murine ERK2 (mERK2) K52A/T183A, which is affinity purified. The substrate, mERK2 K52A T183A, is used to measure MEK1 kinase activity. Recombinant MEK1 enzyme (5 nM) is first activated by 0.02 unit or 1.5 nM of RAF1 in the presence of 25 mM HEPES (pH 7.8), 1 mM MgCl2, 50 mM NaCl, 0.2 mM EDTA, and 50 μM ATP for 30 minutes at 25 °C. In a total volume of 20 μL, the reactions are started by adding 2 μM of mERK2K52A T183A and 2.5 μCi [γ-33P] ATP. Similar methods are used to measure the activity of MEK2 kinase, with the exception that 11 nM of the active MEK2 enzyme is used in the assays instead of activation by RAF1. Invitrogen uses its Select Screen Kinase Profiling Service to carry out kinase profiling. The Z'-LYTE biochemical assay is employed. RDEA119 is tested in quadruplicate at 10 μM against 205 kinases.
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| Cell Assay |
Cells are plated in white 384-well plates at 1,000/20 μL per well or white 96-well microplates at 4,000/100 μL per well for experiments involving anchorage-dependent growth inhibition. RDEA119 is incubated for 24 hours at 37 °C, 5% CO2, and 100% humidity, followed by 48 hours at 37 °C and a CellTiter-Glo assay. Wells of an "ultralow binding" plate (Corning) are filled with 60 μL of a 0.15% agarose solution in complete RPMI 1640 for the 96-well anchorage-independent growth assay. Then, each well receives 60 μL of complete RPMI 1640 containing 9,000 cells in 0.15% agarose. After 24 hours, 60 μL of a 3 × drug solution in complete RPMI 1640 without agarose are added. After 7 d, 36 μL of 6 × 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)- 2H-tetrazolium, inner salt reagent are added per well. On the M5 plate reader, absorbance at 490 nm is measured after two hours at 37 °C.
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| Animal Protocol |
Mice: Except for the Colo205 study 2, which employed male mice, all efficacy studies used athymic nude female mice. Mice are given s.c. injections of 1×106 tumor cells (Colo205 and A431) or ~1 mm3 tumor fragments (A375 and HT-29). Caliper measurements are used to track tumor volumes. When tumors are 80 to 185 mm3 in size, treatment is started for efficacy analysis. Refametinib (25 and 50 mg/kg/d) is given by oral gavage once daily for 14 days, twice daily for 14 days, or once every two days for 14 doses.
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| References |
| Molecular Formula |
C19H20F3IN2O5S
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| Molecular Weight |
572.34
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| Exact Mass |
572.01
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| Elemental Analysis |
C, 39.87; H, 3.52; F, 9.96; I, 22.17; N, 4.89; O, 13.98; S, 5.60
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| CAS # |
923032-37-5
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| Related CAS # |
Refametinib (R enantiomer);923032-38-6
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| Appearance |
white solid powder
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| SMILES |
COC1=CC(=C(C(=C1NS(=O)(=O)C2(CC2)C[C@@H](CO)O)NC3=C(C=C(C=C3)I)F)F)F
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| InChi Key |
RDSACQWTXKSHJT-NSHDSACASA-N
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| InChi Code |
InChI=1S/C19H20F3IN2O5S/c1-30-15-7-13(21)16(22)18(24-14-3-2-10(23)6-12(14)20)17(15)25-31(28,29)19(4-5-19)8-11(27)9-26/h2-3,6-7,11,24-27H,4-5,8-9H2,1H3/t11-/m0/s1
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| Chemical Name |
N-[3,4-difluoro-2-(2-fluoro-4-iodoanilino)-6-methoxyphenyl]-1-[(2S)-2,3-dihydroxypropyl]cyclopropane-1-sulfonamide
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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: ≥ 2.5 mg/mL (4.37 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. Solubility in Formulation 2: ≥ 2.5 mg/mL (4.37 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (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 corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.7472 mL | 8.7361 mL | 17.4721 mL | |
| 5 mM | 0.3494 mL | 1.7472 mL | 3.4944 mL | |
| 10 mM | 0.1747 mL | 0.8736 mL | 1.7472 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 |
| NCT01764828 | Completed | Drug: Refametinib (BAY86-9766) Drug: Gemcitabine |
Neoplasms | Bayer | February 5, 2013 | Phase 1 |
| NCT02346032 | Completed | Drug: refametinib | Biliary Tract Cancer | Samsung Medical Center | June 30, 2015 | Phase 2 |
| NCT01915589 | Completed | Drug: Refametinib (BAY86-9766) |
Carcinoma, Hepatocellular | Bayer | September 16, 2013 | Phase 2 |
| NCT01915602 | Completed | Drug: Refametinib (BAY86-9766) Drug: Sorafenib (BAY43-9006) |
Carcinoma, Hepatocellular | Bayer | September 27, 2013 | Phase 2 |
| NCT01925638 | Completed | Drug: BAY86-9766 Drug: Ketoconazole |
Drug Interactions | Bayer | September 2013 | Phase 1 |
RDEA119. The IC50s for interaction with MEK1/2 are shown at right.B,view of the ternary complex of human MEK1 bound to Mg-ATP and RDEA119 (PDB: 3E8N) in the active site viewing down.Iverson C, et al. RDEA119/BAY 869766: a potent, selective, allosteric inhibitor of MEK1/2 for the treatment of cancer. Cancer Res. 2009 Sep 1;69(17):6839-47. |
Efficacy of RDEA119 on the growth of human melanoma A375 tumors innu/numice. F
AandB,plasma levels of MEK inhibitor and MEK inhibition in rat brain. |
mouse plasma concentrations of RDEA119 in response to a 25 mg/kg dose and predicted response to 12.5 mg/kg twice daily dose. |
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