Refametinib (RDEA119, Bay 86-9766)

Catalog No.S1089 Synonyms: BAY 869766

Refametinib (RDEA119, Bay 86-9766) Chemical Structure

Molecular Weight(MW): 572.34

Refametinib (RDEA119, Bay 86-9766) is a potent, ATP non-competitive and highly selective inhibitor of MEK1 and MEK2 with IC50 of 19 nM and 47 nM, respectively.

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Cited by 10 Publications

4 Customer Reviews

  • RDEA119 (1 µM) or JTP-74057 (0.1 µM) abolished the effects of G1 on DAPK1 and NR2B phosphorylation.

    J Neurosci, 2012, 32(14): 4887-900. Refametinib (RDEA119, Bay 86-9766) purchased from Selleck.

    Western blot analyses of downstream effector proteins of the MAPK signaling pathway. The panel of CRC cell lines was treated with or without refametinib (1 lM) for 72 h. a-Tubulin served as a loading control.

    Mol Oncol, 2018, 12(8):1398-1409. Refametinib (RDEA119, Bay 86-9766) purchased from Selleck.

  • B: ERK and p-ERK1/2 levels in response to MEKi treatment. Tra = trametinib, Ref = refametinib, Sel = selumetinib, Bin = binimetinib. Films were intentionally overexposed to detect signal in lanes with low p-ERK1/2 expression. For each cell line all treatment conditions were performed as part of the same experiment. All experimental findings were confirmed in independent experiments performed in triplicate. Note: membranes incubated with p-ERK1/2 antibody were overexposed to capture all remaining signal after MEKi treatment. WB images have been cut to keep the same sample order. All membranes incubated with the same antibody have been exposed for the same period of time.

    Am J Cancer Res, 2016, 6(10):2235-2251. Refametinib (RDEA119, Bay 86-9766) purchased from Selleck.

    MEK inhibition of hypoosmolar-induced ADM. In all panels KrasG12D acinar explants were isolated and starved overnight. The next day explants were incubated with hypoosmotic (150 mOsm) medium for 5 min and then refametinib was added at the indicated concentrations. (A) HRP assay from two mice was performed immediately after the 5 min hypoosmotic treatment. Mean ± SD, two-tailed t-test. (B) Acinar explants were seeded in collagen and ADM was quantified at day 4. N = number of mice. Mean ± SD, two-tailed t-test. (C) Representative bright field images of acinar explants described in B. Dashed lines highlight acinar cell clusters, arrowheads: duct-like structures. Scale bars = 50 μm.

    EBioMedicine, 2017, 15:90-99. Refametinib (RDEA119, Bay 86-9766) purchased from Selleck.

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Biological Activity

Description Refametinib (RDEA119, Bay 86-9766) is a potent, ATP non-competitive and highly selective inhibitor of MEK1 and MEK2 with IC50 of 19 nM and 47 nM, respectively.
Targets
MEK1 [1]
(Cell-free assay)
MEK2 [1]
(Cell-free assay)
19 nM 47 nM
In vitro

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. [1] 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. [2]

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. [1]

Protocol

Kinase Assay:

[1]

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MEK 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 Research:

[1]

+ Expand
  • Cell lines: A375, SK-MEI-28, Colo205, HT-29 and BxPC3 cells
  • Concentrations: 10-1000 nM
  • Incubation Time: 48 hours
  • Method:

    For anchorage-dependent growth inhibition experiments, 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.


    (Only for Reference)
Animal Research:

[1]

+ Expand
  • Animal Models: Female athymic nude mice are injected s.c. with A375, HT-29 and A431 tumor; male athymic nude mice with Colo205 tumor.
  • Formulation: RDEA119 is dissolved in saline.
  • Dosages: 25 or 50 mg/kg
  • Administration: Orally once daily for 14 days
    (Only for Reference)

Solubility (25°C)

In vitro DMSO 100 mg/mL (174.72 mM)
Ethanol 100 mg/mL (174.72 mM)
Water Insoluble

* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.

Chemical Information

Molecular Weight 572.34
Formula

C19H20F3IN2O5S

CAS No. 923032-37-5
Storage powder
in solvent
Synonyms BAY 869766

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID