Givinostat (ITF2357) 化学構造
分子量: 475.97

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Quality Control & MSDS

製品説明

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    HDAC製品生物活性の比較
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製品の説明

生物活性

製品説明 Givinostat (ITF2357)はヒストン脱アセチル酵素(HDACs)経口有効阻害剤、 IC50 が 7.5-16 nM.
ターゲット HDAC
IC50 7.5 to 16 nM [1]
In vitro試験 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. [1] 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%. [2] 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. [3]
In vivo試験 ITF2357 (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. [1] ITF2357 (10 mg/kg) significantly prolongs survival of severe combined immunodeficient mice inoculated with the AML-PS in vivo passaged cell line. [2] 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. [4]
臨床試験 A Phase II clinical trial of ITF2357 in active systemic onset juvenile idiopathic arthritis (SOJIA) has been completed.
特集 An orally active, potent inhibitor of histone deacetylases (HDACs).

プロトコル (参考用のみ)

キナーゼアッセイ: [1]

Enzymatic Assay for HDAC Inhibitory Activity of Synthetic Compounds 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).

細胞アッセイ: [1]

細胞株 peripheral blood mononuclear cells (PBMCs)
濃度 1 nM - 1 μM
反応時間 24 hours
実験の流れ 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.

動物実験: [1]

動物モデル Mice. 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.
製剤 Dissolved in water
投薬量 0.01-50 mg/kg
投与方法 By gavage in 100 μL water.

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

SpeciesMouseRatRabbitGuinea pigHamsterDogMonkeyBaboon
Weight (kg)0.020.151.80.40.0810312
Body Surface Area (m2)0.0070.0250.150.050.020.50.240.6
Km factor361285201220
Animal A (mg/kg) = Animal B (mg/kg) multiplied by  Animal B Km
Animal A Km

For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

Rat dose (mg/kg) = mouse dose (22.4 mg/kg) ×  mouse Km(3)  = 11.2 mg/kg
rat Km(6)
1

参考

化学情報

Download Givinostat (ITF2357) SDF
分子量 475.97
化学式

C24H27N3O4.HCl.H2O

CAS No. 732302-99-7
保管 2年-20℃
6月-80℃in solvent
別名 N/A
溶解度 (25°C) * In vitro DMSO 95 mg/mL (199.59 mM)
エタノール 3 mg/mL (6.3 mM)
<1 mg/mL (<1 mM)
In vivo 30% propylene glycol, 5% Tween 80, 65% D5W 30 mg/mL
* <1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.
化学名 (6-((diethylamino)methyl)naphthalen-2-yl)methyl 4-(hydroxycarbamoyl)phenylcarbamate hydrochloride hydrate

カスタマーフィードバック (3)


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Source J Neurosci, 2013, 33(17), 7535-47. Givinostat (ITF2357) purchased from Selleck
Method Immunohistochemistry
Cell Lines Third instar larvae
Concentrations
Incubation Time
Results Only larvae treated with ms-275, Givinostat, and Mocetinostat showed rescue of the axonal transport phenotype (C–F). These results reveal that although the inhibitors tested were classified as similar in terms of the HDAC classes they target, they showed differences in their efficacy for treatment of axonal vesicle stalling and corresponding behavioral defects, in vivo.

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Source J Antimicrob Chemother, 2014, 69(1), 28-33. Givinostat (ITF2357) purchased from Selleck
Method Flow cytometry
Cell Lines CD4+ T cells
Concentrations 200 nM
Incubation Time 4 days
Results Six HDAC inhibitors (vorinostat, TsA, oxamflatin, scriptaid, belinostat, and givinostat) and found that the viral gene expression induced by all six in resting CD4+ T cells was reduced after givinostat treated for 8days.

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Source Dr. Zhang of Tianjin Medical University. Givinostat (ITF2357) purchased from Selleck
Method Western blot
Cell Lines
Concentrations 0-10 μM
Incubation Time
Results Increased Histone acetylation in cells treated with ITF2357 was observed.

文献中の引用 (9)

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description
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