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    Mirdametinib (PD0325901)
    Mirdametinib (PD0325901)

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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 #: V0445
    CAS #: 391210-10-9Purity ≥98%

    Description: Mirdametinib (PD-0325901) is a novel, potent, selective, orally bioavailable and non ATP-competitive inhibitor of the mitogen-activated protein kinase MEK with IC50 of 0.33 nM in cell-free assays, roughly 500-fold more potent than CI-1040 on phosphorylation of ERK1 and ERK2. PD325901 is a derivative of MEK inhibitor CI-1040 that selectively binds to and inhibits MEK, which may result in the inhibition of the phosphorylation and activation of MAPK/ERK and the inhibition of tumor cell proliferation. MEK is a key component of the RAS/RAF/MEK/ERK signaling pathway that is frequently activated in human tumors.

    References: Mol Cancer Ther. 2010 Jul;9(7):1968-76.

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    Molecular Weight (MW)482.19
    FormulaC16H14F3IN2O4
    CAS No.391210-10-9
    Storage-20℃ for 3 years in powder form
    -80℃ for 2 years in solvent
    Solubility (In vitro)DMSO: 96 mg/mL (199.1 mM)
    Water: <1 mg/mL
    Ethanol: 40 mg/mL (83.0 mM)
    Solubility (In vivo)30% PEG 400+5% Tween 80+ddH2O: 10 mg/mL
    SynonymsMirdametinib; PD 0325901; PD-0325901; PD0325901; PD-325901; PD 325901; PD325901; (R)-N-(2,3-dihydroxypropoxy)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzamide



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    In Vitro

    In vitro activity: PF0325901 shows higher permeability than CI-1040, another MEK inhibitor. PD0325901 should be able to achieve higher systemic exposures than CI-1040. PD0325901 is exquisitely specific and highly potent against purified MEK, revealing a Kiapp of 1 nM against activated MEK1 and MEK2. PD0325901 is roughly 500-fold more potent than CI-1040 with respect to its cellular effects on phosphorylation of ERK1 and ERK2, displaying subnanomolar activity. PD0325901 prevents the growth of melanoma cell lines. PD0325901 inhibits the growth of TPC-1 cells and K2 cells with GI50 of 11 nM and 6.3 nM, respectively.  PD0325901 significantly prevents the the growth of PTC cells harboring a BRAF mutation at very low concentration (10 nM) and only moderately increases the growth of the PTC cells carrying the RET/PTC1 rearrangement at the same concentration. PD0325901 effectively inhibits the phosphorylation of ERK1/2 in multiple PTC cell lines.


    Kinase Assay: Incorporation of 32P into myelin basic protein (MBP) is assayed in the presence of a glutathione S-transferase fusion protein containing p44MAP kinase (GST-MAPK) and a glutathione S-transferase protein containing p45MEK (GST-MEK). The assay solution contained 20 mM HEPES, pH 7.4, 10 mM MgCl2, 1 mM MnCl2, 1 mM EGTA, 50 mM [gamma-32P]ATP, 10 mg GST-MEK, 0.5 mg GST-MAPK and 40 mg MBP in a final volume of 100 mL. Reactions are stopped after 20 minutes by addition of trichloroacetic acid and filtered through a GF/C filter mat. 32P retained on the filter mat is determined using a 1205 Betaplate. PD0325901 is assessed at various dose ranges in order to determine dose response curves.


    Cell Assay: PTC cells (1 × 104) are seeded in 24-well plates with 1 mL of medium for 4 days in a 37 °C incubator. MEK inhibitor PD0325901 at varying concentrations is added to the cells in triplicate on day 0. MTT dissolved in 0.8% NaCl solution at 5 mg/mL is added to each well (0.2 mL) on day 2 to test GI50 or every day for cell growth curves. The cells are incubated at 37 °C for 3 hours with MTT. The liquid is then aspirated from the wells and discarded. Stained cells are dissolved in 0.5 mL of DMSO and their absorption at 570 nm is measured using a Synergy HT multidetection microplate reader. For GI50, cell growth is calculated as 100 × (T − T0)/(C − T0), where T is the optical density of the wells treated with inhibitors after a 48-hour period, T0 is the optical density at time zero, and C is the control optical density with DMSO only.

    In VivoThe improved potency of PD0325901 relative to CI-1040 is evident. A single oral dose of PD0325901 (25 mg/kg) inhibits phosphorylation of ERK by more than 50% at 24 hours post-dosing. In contrast, CI-1040 at a much higher dose (150 mg/kg) only inhibit pERK levels for roughly 8 hours, returning to control levels by 24 hours after treatment. Therefore, the dose required to produce a 70% incidence of complete tumor responses (C26 model) is 25 mg/kg/day versus 900 mg/kg/day for PD0325901 and CI-1040, respectively. Anticancer activity of PD 0325901 has been demonstrated for a broad spectrum of human tumor xenografts. After 1 week of oral administration of PD0325901 (20–25 mg/kg/day) in mice, no tumor growth is detected in mice inoculated with PTC cells bearing a BRAF mutation. For PTC with the RET/PTC1 rearrangement, the average tumor volume of the orthotopic tumor is decreased by 58% as compared with controls. In conclusion, PTC cells carrying a BRAF mutation are more sensitive to PD0325901 than are PTC cells carrying the RET/PTC1 rearrangement.
    Animal modelNcr-nu/nu mice bearing PTC cells
    Formulation & DosageDissolved in 80 mM citric buffer (pH 7); 20-25 mg/kg;  Oral gavage
    References

    Mol Cancer Ther. 2010 Jul;9(7):1968-76.


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

    PD0325901

    PD0325901 inhibits PTC cell growth in vitro.  2010 Jul;9(7):1968-76.


    PD0325901

    PD0325901

    PD0325901 suppresses the expression of p-ERK1/2 and induces apoptosis in PTC cells.  2010 Jul;9(7):1968-76.

    PD0325901

    PD0325901 inhibits tumor growth in mice.  2010 Jul;9(7):1968-76.


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