Home MAPK MEK inhibitor Refametinib (RDEA119)

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Refametinib (RDEA119) MEK inhibitor

Cat.No.S1089

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.
Refametinib (RDEA119) MEK inhibitor Chemical Structure

Chemical Structure

Molecular Weight: 572.34

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Chemical Information, Storage & Stability

Molecular Weight 572.34 Formula

C19H20F3IN2O5S

 Storage (From the date of receipt)
CAS No. 923032-37-5 Download SDF Storage of Stock Solutions

Synonyms Bay 86-9766 Smiles COC1=CC(=C(C(=C1NS(=O)(=O)C2(CC2)CC(CO)O)NC3=C(C=C(C=C3)I)F)F)F

Solubility

In vitro
Batch:

DMSO : 100 mg/mL (174.72 mM)
(Moisture-contaminated DMSO may reduce solubility. Use fresh, anhydrous DMSO.)

Ethanol : 100 mg/mL

Water : Insoluble

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Mass Concentration Volume Molecular Weight

In vivo
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Mechanism of Action

Targets/IC50/Ki
MEK1 [1]
(Cell-free assay)
19 nM
MEK2 [1]
(Cell-free assay)
47 nM
In vitro
Refametinib (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. It 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). This compound shows a tissue selectivity that reduces its potential for central nervous system–related side effects. [1] It 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). The inhibitory effect of Refametinib in selected cell lines OCUT1 (BRAF V600E(+), PIK3CA H1047R(+)) and SW1376 (BRAF V600E(+)) is enhanced by combination with the mTOR inhibitor, temsirolimus. It and temsirolimus also show synergistic effects on autophagic death of OCUT1 and KAT18 cells selectively tested. [2]
Kinase Assay
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 for Refametinib (RDEA119) is performed by Invitrogen using their Select Screen Kinase Profiling Service. The Z'-LYTE biochemical assay is used. This compound is assayed in quadruplicate at 10 μM against 205 kinases.
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. This compound at 25 mg/kg on a once daily × 14 schedule results in 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]
References

Applications

Methods Biomarkers Images PMID
Growth inhibition assay IC50 S1089-viability1 29896883
Western blot p-BRAF / BRAF / p-MEK / MEK / p-ERK / ERK Cyclin D1 / Cyclin E / p27 p-STAT3 / STAT3 S1089-WB1 29896883

Clinical Trial Information

(data from https://clinicaltrials.gov, updated on 2024-05-22)

NCT Number Recruitment Conditions Sponsor/Collaborators Start Date Phases
NCT01392521 Completed
Neoplasms
Bayer
 July 2011 Phase 1
NCT00785226 Completed
Advanced Cancer
Bayer
 November 2008 Phase 1|Phase 2

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