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    PD184352 (CI1040)
    PD184352 (CI1040)

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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 #: V0448
    CAS #: 212631-79-3Purity ≥98%

    Description: PD184352 (PD-184352; CI-1040), an analog of benzhydroxamate, is an orally bioactive, specific, allosteric/non-ATP competitive MEK1/2 inhibitor with potential anticancer activity. It inhibits MEK1/2 with IC50s of 17 nM in cell-based assays, and shows 100-fold higher selectivity for MEK1/2 over MEK5.  It shows potent anti-proliferative activity in vitro and high in vivo antitumor efficacy in mouse xenograft models.

    References: Nat Med. 1999 Jul;5(7):810-6; Biochem J. 2000 Oct 1;351(Pt 1):95-105; Cancer Biol Ther. 2005 Nov;4(11):1275-84.

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    Molecular Weight (MW)478.67
    CAS No.212631-79-3
    Storage-20℃ for 3 years in powder form
    -80℃ for 2 years in solvent
    Solubility (In vitro)DMSO: 96 mg/mL (200.6 mM)
    Water: <1 mg/mL
    Ethanol: 14 mg/mL (29.2 mM)
    Solubility (In vivo)30% PEG400+0.5% Tween80+5% propylene glycol, pH 9: 10 mg/mL

    PD 184352; CI-1040; CI1040; PD-184352; PD184352; CI 1040; 

    Chemical Name: 2-(2-Chloro-4-iodophenylamino)-N-(cyclopropylmethoxy)-3,4-difluorobenzamide


    InChi Code: InChI=1S/C17H14ClF2IN2O2/c18-12-7-10(21)3-6-14(12)22-16-11(4-5-13(19)15(16)20)17(24)23-25-8-9-1-2-9/h3-7,9,22H,1-2,8H2,(H,23,24)

    SMILES Code: O=C(NOCC1CC1)C2=CC=C(F)C(F)=C2NC3=CC=C(I)C=C3Cl 

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    In Vitro

    In vitro activity: CI-1040 treatment produces a reduction of pMAPK levels in multiple tumor cells including Colon 26, BX-PC3 pancreatic, A431 cervical, HT-29 colon, ZR-25-1 breast and SKOV-3 ovarian carcinomas. CI-1040 treatment doesn't inhibit the phosphorylation of Jun kinase, p38 kinase or Akt, indicating CI-1040 specifically targets MEK. Inhibition of MAPK activation by CI-1040 prevents cell cycle progression and induces a G1 block. The IC50 for inhibition of MEK1 by CI-1040 is 0.3 μM, 15-fold higher than the concentration required to inhibit the EGF-induced activation of ERK2 in Swiss 3T3 cells. These results indicate CI-1040 exerts its effects on cells by suppressing the activation of MKK1, and not by blocking its activity. 2 nM PD184352 inhibits the activation of MKK1 in Swiss 3T3 cells by 50%, while over 100-fold concentration of CI-1040 inhibits MEK1 in vitro. PD184352 also inhibits the Raf-catalysed phosphorylation of MEK1 without any effect on the Raf-catalysed phosphorylation of myelin basic protein. CI-1040 inhibits 86% of papillary thyroid carcinoma (PTC) cell growth with the RET/PTC1 rearrangement at 10μM compared with cells treated with DMSO only. CI-1040 shows potent inhibition to PTC cells (BRAF mutation) with GI50 of 52 nM, but low activity to RET/PTC1 rearrangement type with GI50 of 1.1 μM. A recent research indicates CI-1040 increases the apoptotic effect of BMS-214662 in a CML blast crisis cell line, K562, and in primary chronic phase CD34+ CML cells.

    Kinase Assay: MAP kinase is activated after phosphorylation by MEK; the activated MAP kinase subsequently phosphorylates myelin basic protein (MBP).Incorporation of 32P into myelin basic protein (MBP) is assayed in the presence of glutathione S-transferase (GST) fusion proteins containing the 44-kDa MAPK (GST-MAPK) or the 45-kDa MEK (GST-MEK1). Assays are conducted in 50μL of 50 mM Tris, pH 7.4/10 mM MgCl2 /2 mM EGTA/10 μM [γ-32P]ATP containing 10 μg of GST-MEK1, 0.5 μg of GST-MAPK, and 40 μg of MBP. After incubation at 30°C for 15 minutes, reactions are stopped by addition of Laemmli SDS sample buffer. Phosphorylated MBP is resolved by SDS/10% PAGE. This screening effort leads to the discovery of several small-molecule inhibitors of MEK, i.e. CI-1040. Experiments assessing the order of addition shows that CI-1040 directly inhibits MEK1 with a 50% inhibitory concentration (IC50) of 17 nM, without affecting the activity of MAPK.

    Cell Assay: Cells (Colon 26 carcinoma cells) are planted seeded in T-75 cm2 flasks and treated the next day for 24 hous with either DMSO or CI-1040. Single-cell suspensions are collected, and pellets are fixed in ice-cold ethanol (70%) for 30 minutes. After centrifugation of the samples, propidium iodide (50 μg/mL) and RNase (30 units/mL) are added to the pellets for 20 minutes at 37 °C. After filtration, samples are analyzed by flow cytometry.

    In VivoOral dosing of CI-1040 impairs the growth of colon tumor xenografts of mouse and human with a wide dose range of 48-200 mg/kg per dose, but not of P388 leukemia. CI-1040 inhibits the tumor xenografts from PTC cells carrying a BRAF mutation with 31.3% reduction, carrying the RET/PTC1 rearrangement with 47.5% reduction than in untreated (vehicle) mice after 3 weeks of oral administration (300 mg/kg/d). No toxic effects are observed in any mice when they are treated with CI-1040. Transient exposure of mammary tumors to CI-1040 and UCN-01 causes tumor cell death in vivo and prolonged suppression of tumor regrowth. Combined treatment with CI-1040 (25 mg/kg) and UCN-01 (0.1-0.2 mg/kg) significantly reduces MDA-MB-231, and largely abolishs MCF7 tumor growth in implanted athymic mice, while either single treatment has no significant activity. The drug combination leads to profound tumor cell death which correlates with a reduction in the phosphorylation of ERK1/2 and the immuno-reactivity of Ki67 and of CD31.
    Animal modelPTC cells in athymic mice
    Formulation & DosageDissolved in Cremophor EL–95% ethanol (50:50) and dilutes with water; 150 mg/kg;  Administered orally

    Nat Med. 1999 Jul;5(7):810-6; Biochem J. 2000 Oct 1;351(Pt 1):95-105; Cancer Biol Ther. 2005 Nov;4(11):1275-84.

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


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