ITF2357 (Givinostat, Gavinostat) is a histone deacetylase inhibitor with potential anti-inflammatory, anti-angiogenic, and antineoplastic activities.The IC50 vale for maize HDAC preparations HD2, HD-1B and HD-1A are 10, 7.5 and 16 nM respectively. ITF2357 (Givinostat, Gavinostat) inhibits class I and class II histone deacetylases (HDACs) and several pro-inflammatory cytokines.This reduces expression of tumour necrosis factor (TNF), interleukin 1α and β, and interleukin 6. ITF2357 (Givinostat,Gavinostat) also has activity against cells expressing JAK (2V617F), a mutated form of the janus kinase 2 (JAK2) enzyme that is implicated in the pathophysiology of many myeloproliferative diseases, including polycythaemia vera.
|Source||Int J Cancer (2014). Figure 3. ITF2357|
|Cell Lines||SU-DHL-4 and DOHH-2 cells|
|Incubation Time||24 h|
|Results||The cytostatic and cytotoxic effects of ITF2357 appeared instead to be more closely associated with c-Myc reduction|
|Cell lines||Purified monocytes|
|Preparation method||Caspase 3/7 Determinations
Monocytes were isolated from freshly obtained unfractionated PBMCs by anti-CD14–labeled magnetic beads (CD14 MicroBeads, Miltenyi Biotec, Bergisch Gladbach, Germany) and incubated at 50,000 cells/well in flat-bottom 96-well plates in the presence of increasing concentrations of ITF2357 for 1 h. Thereafter, LPS (10 ng/mL) was added for an additional 24-h incubation. The activity of caspase 3/7 was then determined by Apo-ONE Homogeneous Caspase-3/7 Assay (Promega), and the amount of fluorescence was detected by fluorimetric plate reader (Victor-2; Perkin Elmer).
|Concentrations||0~ 1000 nM|
|Incubation time||24 h|
|Animal models||ConA-induced hepatitis in BALB/C mice|
|Formulation||One milligram of ITF2357 was added to 1 mL water and heated to 90° C until dissolved|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|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.
Pharmacokinetics, safety and inducible cytokine responses during a phase 1 trial of the oral histone deacetylase inhibitor ITF2357 (givinostat).
Furlan A et al. Mol Med. 2011 May-Jun;17(5-6):353-62. PMID: 21365126.
Inhibition of HDAC activity by ITF2357 ameliorates joint inflammation and prevents cartilage and bone destruction in experimental arthritis.
Joosten LA et al. Mol Med. 2011 May-Jun;17(5-6):391-6. PMID: 21327299.
Effects of the histone deacetylase inhibitor ITF2357 in autoinflammatory syndromes.
Bodar EJ et al. Mol Med. 2011 May-Jun;17(5-6):363-8. PMID: 21274502.
The oral histone deacetylase inhibitor ITF2357 reduces cytokines and protects islet β cells in vivo and in vitro.
Lewis EC et al. Mol Med. 2011 May-Jun;17(5-6):369-77. PMID: 21193899.
ITF2357 interferes with apoptosis and inflammatory pathways in the HL-60 model: a gene expression study.
Galimberti S et al. Anticancer Res. 2010 Nov;30(11):4525-35. PMID: 21115902.
The histone deacetylase inhibitor ITF2357 reduces production of pro-inflammatory cytokines in vitro and systemic inflammation in vivo.
Leoni F, et al. Mol Med. 2005 Jan-Dec;11(1-12):1-15. PMID: 16557334.
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ACY-738 is a potent, selective and orally-bioavailable HDAC6 inhibitor, with an IC50s of 1.7 nM.
HPOB is a highly potent and selective inhibitor of histone deacetylase 6 (HDAC6) with IC50 of 56 nM, >30 fold less potent against other HDACs.
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