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    Givinostat HCl monohydrate (ITF-2357; Gavinostat))
    Givinostat HCl monohydrate (ITF-2357; Gavinostat))

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    产品仅用于科学研究,不针对患者销售
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    InvivoChem目录号 #: V0289
    CAS号码 #: 732302-99-7 纯度 ≥98%

    Description: Givinostat (formerly ITF2357; Gavinostat) is a potent and orally bioavailable inhibitor of both class I and class II histone deacetylase (HDAC) with potential anticancer activity. It inhibits HDAC with IC50s of 198 and 157 nM for HDAC1 and HDAC3, respectively. Givinostat is also a potent inhibitor of hematopoietic colony formation by JAKEV617F-bearing progenitor cells from chronic myeloproliferative neoplasms in vitro. 

    References: Mol Med. 2005 Jan-Dec;11(1-12):1-15; Leukemia. 2007 Sep;21(9):1892-900; Mol Med. 2011 May-Jun;17(5-6):369-77.

    Related CAS: 732302-99-7 (HCl hydrate); 497833-27-9 (free base); 199657-29-9 (HCl)

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    Molecular Weight (MW)475.97
    FormulaC24H27N3O4.HCl.H2O
    CAS No.732302-99-7 (HCl monohydrate); 
    Storage-20℃ for 3 years in powder form
    -80℃ for 2 years in solvent
    Solubility (In vitro)DMSO: 95 mg/mL (199.6 mM)
    Water: <1 mg/mL
    Ethanol: 3 mg/mL (6.3 mM)
    Solubility (In vivo)30% propylene glycol, 5% Tween 80, 65% D5W: 30 mg/mL
    Synonyms

    ITF2357; ITF 2357; ITF-2357; Givinostat ; gavinostat; ITF2357 HCl; ITF2357 hydrochloride; Givinostat HCl

    Chemical Name: (6-((diethylamino)methyl)naphthalen-2-yl)methyl (4-(hydroxycarbamoyl)phenyl)carbamate hydrochloride hydrate

    InChi Key: FKGKZBBDJSKCIS-UHFFFAOYSA-N

    InChi Code: InChI=1S/C24H27N3O4.ClH.H2O/c1-3-27(4-2)15-17-5-7-21-14-18(6-8-20(21)13-17)16-31-24(29)25-22-11-9-19(10-12-22)23(28)26-30;;/h5-14,30H,3-4,15-16H2,1-2H3,(H,25,29)(H,26,28);1H;1H2

    SMILES Code: ONC(C1=CC=C(C=C1)NC(OCC2=CC3=C(C=C2)C=C(CN(CC)CC)C=C3)=O)=O.[H]Cl.[H]O[H] 


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    In Vitro

    In vitro activity: In LPS-stimulated cultured human peripheral blood mononuclear cells (PBMCs), ITF2357 reduces the release of TNFα, IL-1α, IL-1β, and IFNγ, with IC50 of 10-25 nM, respectively. Using the combination of IL-12 plus IL-18, ITF2357 reduces IFNγ and IL-6 production with IC50 of 12.5-25 nM, independent of decreased IL-1 or TNFα. ITF2357 is cytotoxic in multiple myeloma (MM) cell lines (RPMI8226, NCI-H929, JJN3, KMS 11, KMS 12, KMS 18, and KMS 20) and acute myelogenous leukemia (AML) cell lines (HL-60, THP-1, U937, KASUMI, KG-1, and TF-1), with IC50 of 200 nM. ITF2357 activates the intrinsic apoptotic pathway, upregulates p21 and downmodulates Bcl-2 and Mcl-1. ITF2357 inhibits the production of IL-6, VEGF, and IFNγ in mesenchymal stromal cells (MSCs) by 80-95%. ITF2357 favors β-cell survival during inflammatory conditions. ITF2357 at concentrations of 25 and 250 nM increases islet cell viability, enhances insulin secretion, inhibits release of MIP-1α and MIP-2, reduces NO production and decreases apoptosis rates.


    Kinase Assay: The assay is performed by adding 100 μL substrate (2×105 cpm), 40 μL buffer (50 mM Tris-HCl, pH 8.0, 750 mM NaCl, 5 mM PMSF, 50% glycerol) and 95 μL distilled water to the crude cellular extract (5 μL). ITF2357 (50 μL) is added to test for HDAC inhibition. The mixture is incubated overnight at room temperature and the reaction quenched by adding 50 μL of a solution containing 259 μL 37% HCl and 28 μL acetic acid in 1 mL distilled water. The [3H]acetyl residues released from the substrate are separated by organic extraction with 600 μL of ethyl acetate, 200 μL of the organic phase is added to standard scintillation fluid, and radioactivity is measured by a beta-counter. Inhibition of HDACs is expressed as the concentration inhibiting 50% of the control activity (by comparing the radioactivity of the samples containing inhibitors to that of the control containing cellular crude extract alone).


    Cell Assay: After washing, the isolated PBMCs are resuspended in RPMI containing 5% FCS at 5×106/mL, added to a 50-mL conical polypropylene tube, and placed at 4 °C overnight. The PBMCs are resuspended the next morning and added to a 96-well flat microtiter plate (100 μL per well). ITF2357 is then added for inhibition studies, and the plates are incubated at 37 °C for 1 hour, after which the cells are stimulated with LPS or other stimulants in a final volume of 200 μL per well. The supernatants are removed after incubation at 37 °C for 24 hours, and frozen at -80 °C until assayed for cytokines.

    In VivoITF2357 (1-10 mg/kg) reduces LPS-induced serum TNFα and IFNγ by more than 50% in mice. Anti-CD3-induced cytokines are not suppressed by ITF2357 in PBMCs in the circulation in mice. In concanavalin-A-induced hepatitis, ITF2357 (1 or 5 mg/kg) significantly reduces liver damage. ITF2357 (10 mg/kg) significantly prolongs survival of severe combined immunodeficient mice inoculated with the AML-PS in vivo passaged cell line. In a mouse model of closed head injury (CHI), ITF2357 (10 mg/kg) improves neurobehavioral recovery, decreases neuronal degeneration, reduces lesion volume, and induces glial apoptosis.
    Animal modelMice. For LPS induction of serum cytokines: BALB/c; for anti-CD3-induced cytokines: CD1; for concanavalin A (Con A)-induced acute hepatitis: BALB/c or C57Bl6.
    Formulation & DosageDissolved in water; 0.01-50 mg/kg; Administered in 100 μL water.
    References

    Mol Med. 2005 Jan-Dec;11(1-12):1-15; Leukemia. 2007 Sep;21(9):1892-900; Mol Med. 2011 May-Jun;17(5-6):369-77.


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

    Givinostat (ITF2357)

    Givinostat (ITF2357)

    Effects of oral ITF2357 on STZ-induced β-cell toxicity, serum nitric oxide levels and spleen cell responses in vivo. Mol Med. 2011 May-Jun;17(5-6):369-77. 

    Givinostat (ITF2357)

    Effect of HDAC inhibition on cytokine-induced INS-1 cell death. Mol Med. 2011May-Jun;17(5-6):369-77. 

    Givinostat (ITF2357)

    Givinostat (ITF2357)

    ITF2357 protects from cytokine-induced islet injury in vitro. Mol Med. 2011 May-Jun;17(5-6):369-77. 


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