Givinostat (ITF2357)

Catalog No.S2170 Batch:S217002

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Technical Data

Formula

C24H27N3O4.HCl.H2O
Molecular Weight 475.97 CAS No. 732302-99-7
Solubility (25°C)* In vitro DMSO 95 mg/mL (199.59 mM)
Ethanol 6 mg/mL (12.6 mM)
Water Insoluble
* <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.
* Room temperature shipping (Stability testing shows this product can be shipped without any cooling measures.)

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Biological Activity

Description Givinostat (ITF2357) is a potent HDAC inhibitor for maize HD2, HD1B and HD1A with IC50 of 10 nM, 7.5 nM and 16 nM in cell-free assays. Phase 2.
Targets
HD1-B [1]
(Cell-free assay)		 HD2 [1]
(Cell-free assay)		 HD1-A [1]
(Cell-free assay)
7.5 nM 10 nM 16 nM
In vitro 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 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]
Features An orally active, potent inhibitor of histone deacetylases (HDACs).

Protocol (from reference)

Kinase Assay:[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).
Cell Assay:[1]
  • Cell lines

    peripheral blood mononuclear cells (PBMCs)

  • Concentrations

    1 nM - 1 μM

  • Incubation Time

    24 hours

  • Method

    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.
Animal Study:[1]
  • Animal Models

    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.

  • Dosages

    0.01-50 mg/kg

  • Administration

    By gavage in 100 μL water.

Customer Product Validation

Data from [Data independently produced by J Antimicrob Chemother, 2014, 69(1), 28-33]

Data from [Data independently produced by J Neurosci, 2013, 33(17), 7535-47]

, , Dr. Zhang of Tianjin Medical University

Data from [Data independently produced by , , Diabetologia, 2018, 61(2):389-398]

Selleck's Givinostat (ITF2357) has been cited by 33 publications

Propionate functions as a feeding-state-dependent regulatory metabolite to counter pro-inflammatory signaling linked to nutrient load and obesity [ J Leukoc Biol, 2024, qiae006] PubMed: 38207130
Differentiation of crescent-forming kidney progenitor cells into podocytes attenuates severe glomerulonephritis in mice [ Sci Transl Med, 2022, 14(657):eabg3277] PubMed: 35947676
Landscape of immune-related signatures induced by targeting of different epigenetic regulators in melanoma: implications for immunotherapy [ J Exp Clin Cancer Res, 2022, 41(1):325] PubMed: 36397155
Dual Blockade of Misfolded Alpha-Sarcoglycan Degradation by Bortezomib and Givinostat Combination [ Front Pharmacol, 2022, 13:856804] PubMed: 35571097
Dual Blockade of Misfolded Alpha-Sarcoglycan Degradation by Bortezomib and Givinostat Combination [ Front Pharmacol, 2022, 13:856804] PubMed: 35571097
Deep learning detects cardiotoxicity in a high-content screen with induced pluripotent stem cell-derived cardiomyocytes [ Elife, 2021, 10e68714] PubMed: 34338636
Neuroprotective effects of some epigenetic modifying drugs' on Chlamydia pneumoniae-induced neuroinflammation: A novel model [ PLoS One, 2021, 16(11):e0260633] PubMed: 34847172
Prolonged unfolded protein reaction is involved in the induction of chronic myeloid leukemia cell death upon oprozomib treatment [ Cancer Sci, 2020, 112(1):133-143] PubMed: 33067904
Detection of Pathogenic Isoforms of IKZF1 in Leukemic Cell Lines and Acute Lymphoblastic Leukemia Samples: Identification of a Novel Truncated IKZF1 Transcript in SUP-B15 [ Cancers (Basel), 2020, 12(11)E3161] PubMed: 33126432
Combining DNMT and HDAC6 inhibitors increases anti-tumor immune signaling and decreases tumor burden in ovarian cancer. [ Sci Rep, 2020, 10(1):3470] PubMed: 32103105

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SHIPPING AND STORAGE
Selleck products are transported at room temperature. If you receive the product at room temperature, please rest assured, the Selleck Quality Inspection Department has conducted experiments to verify that the normal temperature placement of one month will not affect the biological activity of powder products. After collecting, please store the product according to the requirements described in the datasheet. Most Selleck products are stable under the recommended conditions.

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