Refametinib

SKU: orb1300596

Description

Refametinib (RDEA119) is a potent and selective, ATP-noncompetitive inhibitor of MEK1 and MEK2 kinases, exhibiting IC50 values of 19 nM and 47 nM, respectively. It is widely used in cancer research, demonstrating antitumor activity in both in vitro cellular assays and in vivo models of various malignancies.

Research Area

Signal Transduction

Key Properties

• CAS Number: 923032-37-5
• MW: 572.34
• Purity: 99.93%
• Formula: C₁₉H₂₀F₃IN₂O₅S
• SMILES: S(NC1=C(NC2=C(F)C=C(I)C=C2)C(F)=C(F)C=C1OC)(=O)(=O)C3(C[C@@H](CO)O)CC3
• Target: MEK
• Solubility: Ethanol:93 mg/mL (162.49 mM);DMSO:150 mg/mL (262.08 mM);H2O:< 1 mg/mL (insoluble or slightly soluble)

Bioactivity

• Target IC50:
  MEK1:19 nM|MEK2:47 nM
• In Vivo:
  Oral administration of RDEA119 at 50 mg/kg on a once daily x 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 x 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 x 14 produces 56% and 67% TGI for HT-29 and A431 tumors, respectively.
• 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. 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.
• Cell Research:
  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)

Storage & Handling

• Storage: Powder: -20°C for 3 years | In solvent: -80°C for 1 year | Shipping with blue ice/Shipping at ambient temperature.
• Expiration Date: 12 months from date of receipt.
• Disclaimer: For research use only

Alternative Names

tumor, RDEA119, RDEA-119, Refametinib, RDEA 119, MAP2K, MAPKK, MEK, MEK1, MEK2, Inhibitor, inhibit, Mitogen-activated protein kinase kinase, orally, BAY 869766, BAY 86-97661, BAY869766, BAY-869766, allosteric

Compound Identifiers

PubChem CID

44182295