Givinostat (ITF2357)

For research use only.

Catalog No.S2170

24 publications

Givinostat (ITF2357) Chemical Structure

CAS No. 732302-99-7

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.

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Selleck's Givinostat (ITF2357) has been cited by 24 publications

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Choose Selective HDAC Inhibitors

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.
Features An orally active, potent inhibitor of histone deacetylases (HDACs).
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]

Assay
Methods Test Index PMID
Western blot
SOD2(K68) / SOD2 / p53(K120) / p53(K382) / p53 / p65(K310) / p65; 

PubMed: 26217084     


Effects of givinostat on the post-translational modifications of superoxide dismutase (SOD)2, p53, nuclear factor (NF)-κB, and p65 were analyzed by Western blotting. SOD2 (acetyl K68) acetylation was upregulated, while the expression profile of SOD2 protein showed no significant change. The ratios show a significant difference when compared with those in the control group, in particular at 24 h. Similarly, acetylation of NF-κB p65 (acetyl K310) was upregulated, while its protein expression showed no significant change. There were no obvious changes in the expression profiles of p53, p53 (acetyl K382), and p53 (acetyl K120);

pERK / ERK / pJNK / JNK / pp38 / p38 ; 

PubMed: 26217084     


Expression of extracellular signal-regulated kinase (ERK)1/2, phosphorylated ERK1/2, p38, and phosphorylated p38 was upregulated after lipopolysaccharide (LPS) treatment; in contrast, givinostat inhibited the upregulated expression of phosphorylated ERK1/2 and phosphorylated P38 induced by LPS in a time-dependent manner, while no obvious effect on c-Jun N-terminal kinase (JNK)1/2 and phosphorylated JNK1/2 was found.

PARP / Cleaved PARP / Pro-Caspase 7 / Cleaved caspase 7 / Pro-caspase 3 / Cleaved Caspase 3; 

PubMed: 28050230     


Western blotting of cultured cells treated with or without Givinostat (0.25μM) to reveal activation of apoptotic cascade in Ph+ leukemia cells. The data represents one of three repeats. The cleaved forms of caspase-3 were at 17 kDa, caspase-7 at 20 kDa, and PARP1 at 85 KDa. PARP1, Poly (ADP-Ribose) Polymerase 1; C7 Caspase 7; C3: Caspase 3; GAPDH: Glyceraldehyde-3-Phosphate Dehydrogenase.

CHK1 / p53 / p21; 

PubMed: 28050230     


Western blotting of cultured cells treated with or without Givinostat (0.25μM) to reveal p53 integrality in SUP-B15 (left) and K562 (right) at 24 to 72hrs. GAPDH: Glyceraldehyde-3-Phosphate Dehydrogenase.

α-SMA / TGF-β1 / VEGF ; 

PubMed: 26217084     


In JS-1 cells, treatment with givinostat for 24 h or 48 h significantly suppressed expression of α-smooth muscle actin (SMA), transforming growth factor (TGF)-β1 and Vascular endothelial growth factor (VEGF) compared with the control group. aP < 0.05, bP < 0.01 vs control group.

26217084 28050230
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]

Protocol

Kinase Assay:[1]
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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 Research:[1]
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  • 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.
    (Only for Reference)
Animal Research:[1]
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  • 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.
    (Only for Reference)

Solubility (25°C)

In vitro DMSO 95 mg/mL (199.59 mM)
Water Insoluble
Ethanol '3 mg/mL
In vivo Add solvents to the product individually and in order(Data is from Selleck tests instead of citations):
30% propylene glycol, 5% Tween 80, 65% D5W
For best results, use promptly after mixing.
30 mg/mL

* 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.

Chemical Information

Molecular Weight 475.97
Formula

C24H27N3O4.HCl.H2O

CAS No. 732302-99-7
Storage powder
in solvent
Synonyms N/A
Smiles CCN(CC)CC1=CC2=C(C=C1)C=C(C=C2)COC(=O)NC3=CC=C(C=C3)C(=O)NO.O.Cl

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Clinical Trial Information

NCT Number Recruitment interventions Conditions Sponsor/Collaborators Start Date Phases
NCT01901432 Completed Drug: Givinostat Polycythemia Vera Italfarmaco October 2013 Phase 1|Phase 2
NCT01761292 Completed Drug: Givinostat Duchenne Muscular Dystrophy (DMD) Italfarmaco April 2013 Phase 1|Phase 2
NCT00792506 Terminated Drug: ITF2357 Multiple Myeloma Italfarmaco October 2008 Phase 2
NCT00792467 Completed Drug: ITF2357 Hodgkin''s Lymphoma Italfarmaco February 2008 Phase 1|Phase 2
NCT00792831 Terminated Drug: ITF2357 Chronic Lymphocytic Leukemia Italfarmaco February 2008 Phase 2
NCT00792740 Terminated Drug: ITF2357|Drug: Placebo capsules Crohn''s Disease Italfarmaco October 2007 Phase 1|Phase 2

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID