Molecular Weight(MW): 475.97
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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Representative confocal images of motor axons directly posterior to brains in third instar larvae co-expressing a synaptotagmin-e-GFP fusion protein (syt-eGFP) along with dTip60E431Q under the control of the pan neuronal elav-GAL4 driver reared on food treated with either no drug, ms-275, Givinostat.
J Neurosci 2013 33(17), 7535-47. Givinostat (ITF2357) purchased from Selleck.
Cells were treated with indicated HDAC inhibitors for 4 days and then cultured without drug for an additional 4 days. On day 8, HDAC inhibitors were added back to the culture for another 4 days. The percentage of GFP-positive cells was measured at days 4, 8 and 12. The concentrations of HDAC inhibitors used for the experiments are as follows: vorinostat, 1 uM; TsA, 200 nM; oxamflatin, 1 uM; scriptaid, 1 uM; belinostat, 200 nM; and givinostat, 200 nM. The fraction of GFP-positive cells was measured by flow cytometry at the indicated timepoints. The effect of HDAC inhibitors or anti-CD3 plus anti-CD28 antibodies over time was normalized to the effect of anti-CD3 plus anti-CD28 antibodies at day 2. Error bars represent SEM, n = 3. APHA, 3-(1-methyl-4-phenylacetyl-1H-2-pyrrolyl)-N-hydroxypropenamide.
J Antimicrob Chemother 2014 69(1), 28-33. Givinostat (ITF2357) purchased from Selleck.
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2. For more details, such as half maximal inhibitory concentrations (IC50s) and working concentrations of each inhibitor, please click on the link of the inhibitor of interest.
3. "+" indicates inhibitory effect. Increased inhibition is marked by a higher "+" designation.
4. Orange "√" refers to compounds which do inhibitory effects on the related isoform, but without specific value.
|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).|
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. 
|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.  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. |
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).
|In vitro||DMSO||95 mg/mL (199.59 mM)|
|Ethanol||3 mg/mL (6.3 mM)|
|In vivo||30% propylene glycol, 5% Tween 80, 65% D5W||30 mg/mL|
* 1 mg/ml means slightly soluble or insoluble.
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Clinical Trial Information
|NCT Number||Recruitment||Conditions||Sponsor/Collaborators||Start Date||Phases|
|NCT02851797||Not yet recruiting||Duchenne Muscular Dystrophy||Italfarmaco|inVentiv Health Clinical||October 2016||Phase 3|
|NCT01901432||Recruiting||Polycythemia Vera||Italfarmaco||October 2013||Phase 1|Phase 2|
|NCT01761292||Active, not recruiting||Duchenne Muscular Dystrophy (DMD)||Italfarmaco||May 2013||Phase 1|Phase 2|
|NCT01761968||Recruiting||Chronic Myeloproliferative Neoplasms||Italfarmaco||March 2013||Phase 2|
|NCT01557452||Terminated||Juvenile Idiopathic Arthritis||Italfarmaco|Parexel||December 2011||--|
|NCT01261624||Terminated||Polyarticular Course Juvenile Idiopathic Arthritis||Italfarmaco||October 2010||Phase 2|
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