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    Refametinib (RDEA119, BAY86-9766)
    Refametinib (RDEA119, BAY86-9766)

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    This product is for research use only, not for human use. We do not sell to patients.
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    InvivoChem Cat #: V0461
    CAS #: 923032-37-5Purity ≥98%

    Description: Refametinib (formerly RDEA-119, BAY 86-9766) is an orally bioavailable, highly selective and non-ATP-competitive (allosteric) inhibitor of MEK1/2 with potential antitumor activity. It inhibits MEK1/2with IC50s of 19 nM and 47 nM, respectively. It exhibits excellent anti-proliferative activity in vitro against cancer cell lines harboring V600E BRAF mutant, with GI50 values ranging from 67nM to 89nM. Furthermore, Refametinib demonstrated high in vivo antitumor efficacy in the human melanoma A375 tumor xenograft model and caused obvious tumor growth regression.

    References: Cancer Res. 2009 Sep 1;69(17):6839-47; Int J Cancer. 2010 Dec 15;127(12):2965-73.

    Related CAS: 923032-38-6 (Refametinib R enantiomer)

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    Molecular Weight (MW)572.34
    FormulaC19H20F3IN2O5S
    CAS No.923032-37-5
    Storage-20℃ for 3 years in powder form
    -80℃ for 2 years in solvent
    Solubility (In vitro)DMSO: 100 mg/mL (174.7 mM)
    Water: <1 mg/mL
    Ethanol: 100 mg/mL (174.7 mM)
    Other infoIChemical Name: (S)-N-(3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl)cyclopropane-1-sulfonamide
    InChi Key: RDSACQWTXKSHJT-NSHDSACASA-N
    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
    SMILES Code: O=S(C1(C[[email protected]](O)CO)CC1)(NC2=C(OC)C=C(F)C(F)=C2NC3=CC=C(I)C=C3F)=O
    SynonymRDEA119, Bay 86-9766; RDEA119; RDEA 119; BAY 869766; BAY-69766; BAY869766; BAY 86 9766; BAY 86-9766; BAY869766; RDEA-119; 


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    In Vitro

    In vitro activity: RDEA119 is selectively bound directly to an allosteric pocket in the MEK1/2 enzymes, and highly efficacious at inhibiting cell proliferation in several tumor cell lines, including A375, SK-MEI-28, Colo205, HT-29 and BxPC3. RDEA119 inhibits anchorage-dependent growth of human cancer cell lines harboring the gain-of-function V600E BRAF mutant with GI50 values ranging from 67 to 89 nM. Under anchorage-independent conditions, GI50 values for all cell lines tested are similar (40-84 nM). RDEA119 shows a tissue selectivity that reduces its potential for central nervous system–related side effects. RDEA119 potently inhibits the proliferation of the 4 cell lines that harbored BRAF mutation but has no or modest effects on the other 4 cells that harbored wild-type BRAF (IC50 of 0.034-0.217 μM vs. 1.413-34.120 μM). This inhibitory effect of RDEA119 in selected cell lines OCUT1 (BRAF V600E(+), PIK3CA H1047R(+)) and SW1376 (BRAF V600E(+)) is enhanced by combination with the mTOR inhibitor, temsirolimus. RDEA119 and temsirolimus also show synergistic effects on autophagic death of OCUT1 and KAT18 cells selectively tested.


    Kinase Assay: Kinase inactive murine ERK2 (mERK2) K52A/T183A is affinity purified from Escherichia coli expressed using the pET21a vector. MEK1 kinase activity is determined using mERK2 K52A T183A as the substrate. 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. The reactions are initiated by adding 2 μM of mERK2K52A T183A and 2.5 μCi [γ-33P] ATP in a total volume of 20 μL. The MEK2 kinase activity is determined similarly except that activation by RAF1 is not needed and 11 nM of MEK2 enzyme (active) are used in the assays.Kinase profiling is performed by Invitrogen using their Select Screen Kinase Profiling Service. The Z'-LYTE biochemical assay is used. RDEA119 is assayed in quadruplicate at 10 μM against 205 kinases.


    Cell Assay: For anchorage-dependent growth inhibition experiments, cells (A375, SK-MEI-28, Colo205, HT-29 and BxPC3 cells) are plated in white 384-well plates at 1,000/20 μL/well or white 96-well microplates at 4,000/100 μL/well. After 24-h incubation at 37 °C, 5% CO2, and 100% humidity, RDEA119 is incubated for 48 hours at 37 °C and assayed using CellTiter-Glo. For the 96-well anchorage-independent growth assay, wells of an “ultralow binding” plate (Corning) are filled with 60 μL of a 0.15% agarose solution in complete RPMI 1640. Then, 60 μL of complete RPMI 1640 containing 9,000 cells in 0.15% agarose are added per well. After 24 hour, 60 μL of a 3 × drug solution in agarose-free complete RPMI 1640 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. After 2 hours at 37 °C, absorbance at 490 nm is determined on the M5 plate reader.

    In Vivo Oral administration of RDEA119 at 50 mg/kg on a once daily × 14 schedule leads to a 68% tumor growth inhibition (TGI) in human melanoma A375 tumor model. Oral administration of RDEA119 at 25 mg/kg on a once a once daily × 14 schedule leads to a 123% TGI in human colon carcinoma Colo205 tumor model (TGI > 100% occurs when the tumor shrinks below its starting volume). A dose of 25 mg/kg once daily × 14 produces 56% and 67% TGI for HT-29 and A431 tumors, respectively.
    Animal model Female athymic nude mice are injected s.c. with A375, HT-29 and A431 tumor; male athymic nude mice with Colo205 tumor.
    Formulation & DosageDissolved in saline; 25 or 50 mg/kg; p.o.
    References

    Cancer Res. 2009 Sep 1;69(17):6839-47; Int J Cancer. 2010 Dec 15;127(12):2965-73.


    These protocols are for reference only. InvivoChem does not independently validate these methods.

    Refametinib (Bay 86-9766)

    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.

    Refametinib (Bay 86-9766)

    Efficacy of RDEA119 on the growth of human melanoma A375 tumors in nu/nu mice. F


    Refametinib (Bay 86-9766)

    A and B, plasma levels of MEK inhibitor and MEK inhibition in rat brain.

    Refametinib (Bay 86-9766)

    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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