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    IOX2
    IOX2

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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 #: V0295
    CAS #: 931398-72-0Purity ≥98%

    Description: IOX2 is a novel and potent inhibitor of hypoxia-inducible factor (HIF-1α) prolyl hydroxylase-2 (PHD2) with considerable medical uses. It inhibits PHD2 with an IC50 of 21 nM in a cell-free assay,and displays >100-fold selectivity over JMJD2A, JMJD2C, JMJD2E, JMJD3, or the 2OG oxygenase FIH. 

    References: J Comb Chem. 2010 Sep 13;12(5):676-86; J Biol Chem. 2011 Apr 15;286(15):13041-51.

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    Molecular Weight (MW)

    352.34

    Formula

    C19H16N2O5 

    CAS No.

    931398-72-0

    Storage

    -20℃ for 3 years in powder form

    -80℃ for 2 years in solvent

    Solubility (In vitro)

    DMSO: 7 mg/mL (19.9 mM)

    Water: <1 mg/mL

    Ethanol: <1 mg/mL

    Solubility (In vivo)

    Chemical Name: N-[[1,2-Dihydro-4-hydroxy-2-oxo-1-(phenylmethyl)-3-quinolinyl]carbonyl]glycine

    InChi Key: CAOSCCRYLYQBES-UHFFFAOYSA-N

    InChi Code: InChI=1S/C19H16N2O5/c22-15(23)10-20-18(25)16-17(24)13-8-4-5-9-14(13)21(19(16)26)11-12-6-2-1-3-7-12/h1-9,24H,10-11H2,(H,20,25)(H,22,23)

    SMILES Code: O=C(O)CNC(C1=C(O)C2=C(N(CC3=CC=CC=C3)C1=O)C=CC=C2)=O

    Synonyms

    IOX-2; IOX2; IOX 2


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    In Vitro

    In vitro activity: IOX2 potently inhibits PHD2 (IC50 of 21 nM) with over 100-fold selectivity compared to inhibition of JMJD2A, JMJD2C, JMJD2E, JMJD3, or the 2OG oxygenase FIH (IC50s<100 μM). IOX2 is active in cells, inhibiting HIF-1α hydroxylation in RCC4 cells at 50 μM. Hypoxia Inducible Factor (HIF) is regulated by the hydroxylation of prolyl residues in oxygen-dependent degradation domains in the HIF-1α subunit, which mark it for degradation by the proteosome. 1,2 HIF prolyl hydroxylation is catalyzed by prolyl hydroxylase domain enzymes (PHD1, 2, and 3), members of the Fe(II) and 2-oxoglutarate (2OG) oxygenase family. They require dioxygen as a cosubstrate, thus acting as the hypoxia-sensing component of the HIF system. The activity of PHD is suppressed by hypoxia, increasing both the abundance and activity of the HIF transcriptional complex.

     

    Kinase Assay: All reagents were diluted in 50 mM HEPES, 0.1 % BSA, pH 7.5 supplemented with 0.01 % Tween20 and allowed to equilibrate to room temperature prior to addition to plates. Catalytic turnover assays were run in 10 μM volumes in low-volume 384-well plates at RT. The reaction consisted of enzyme (0.5 ~ 25 nM), biotinylated substrate peptide (30 ~ 1000 nM), Fe(II) (1 ~ 10 μM), Ascorbate (100 μM), 2OG (5 ~ 40 μM) and run at RT. EDTA was used to quench the reaction (5 μM) and AlphaScreen donor (Streptavidin-conjugated) and acceptor (ProteinA-conjugated) beads preincubated with peptide product antibodies were added (5 μM). Plates were foil-sealed to protect from light, incubated at room temperature for 60 mins and read on a PHERAstar FS plate reader using an AlphaScreen 680 excitation/570 emission filter set. The final bead concentration in 20 μM reaction was 20 μM/mL. IC50 values were calculated in Prism 5.

     

    Cell Assay: In RCC4 cells, IOX2 inhibited HIF-1α hydroxylation at 50 μM.

    In Vivo

    To investigate the utility of IOX2 as in vivo functional probes, IOX2 is tested to upregulate HIF signaling in a whole organism, that is, transgenic zebrafish (Danio rerio). Because the expression of the PHD3 encoding gene is regulated by HIF in humans and zebrafish, PHD3 levels are a readout of HIF activity. A zebrafish hypoxia reporter line is generated expressing GFP with the phd3 promoter elements. Transgenic wild-type embryos at 3 days postfertilization treated with compounds (10 μM) for 2 days displayed clear increase in phd3:EGFP expression in the liver, relative to controls. Significant increases in GFP levels are observed with IOX2

    Animal model

    Zebrafish: Phd3:gfpsh144/sh144 fish (Danio rerio) are incrossed to produce phd3:gfpsh144/sh144 embryos, these are raised at 28°C in E3 medium. The phd3:gfpsh144/sh144 line is a hypoxia reporter line created by BAC recombination of the phd3 reporter GFP construct. At 3 days post fertilization, potential inhibitors (e.g., IOX2) are added in fresh medium at 10 μM in 1% DMSO. The embryos are incubated with the compounds for a further 48 h. Embryos are anesthetized at 5 dpf by immersion in tricaine. Lateral view images of the embryos are taken using a fluorescent dissecting stereomicroscope (both bright-field and fluorescent). Fluorescent images are analyzed using Image J.

    Formulation & Dosage

    10 μM in 1% DMSO

    References

    J Comb Chem. 2010 Sep 13;12(5):676-86; J Biol Chem. 2011 Apr 15;286(15):13041-51; EMBO J. 2003 Aug 15;22(16):4082-90.


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

    IOX2

    J Biol Chem. 2011 Apr 15;286(15):13041-51.

    IOX2

    Levels of HIF asparaginyl hydroxylation in hypoxic cells and in rat and human tissues. J Biol Chem. 2011 Apr 15;286(15):13041-51.

    IOX2

    Differential inhibition of HIF prolyl and asparaginyl hydroxylation by HIF hydroxylase inhibitors. J Biol Chem. 2011 Apr 15;286(15):13041-51.


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