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| 25mg |
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Purity: ≥98%
Givinostat (formerly known as ITF-2357; Gavinostat) is a potent and orally bioactive inhibitor of both class I and class II histone deacetylase (HDAC) with potential anti-inflammatory, anti-angiogenic, and anticancer activities. Additionally, it is a strong inhibitor of the in vitro formation of hematopoietic colonies by progenitor cells bearing JAKEV617F from chronic myeloproliferative neoplasms. After p21 is induced and Bcl-2 and Mcl-1 proteins are down-regulated, ITF2357 causes apoptosis in multiple myeloma (MM) and acute myelogenous leukemia (AML) cells. It also prevents peripheral blood mononuclear cells from producing pro-inflammatory cytokines.
| Targets |
hHDAC3 (IC50 = 157 nM); hHDAC1 (IC50 = 198 nM); hHDAC11 (IC50 = 292 nM); hHDAC6 (IC50 = 315 nM); hHDAC2 (IC50 = 325 nM); hHDAC10 (IC50 = 340 nM); hHDAC7 (IC50 = 524 nM); hHDAC5 (IC50 = 532 nM); hHDAC9 (IC50 = 541 nM); hHDAC8 (IC50 = 854 nM); hHDAC4 (IC50 = 1059 nM); HD1-B (IC50 = 7.5 nM); HD1-A (IC50 = 16 nM); HD2 (IC50 = 10 nM)
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| ln Vitro |
Givinostat (ITF2357) effectively inhibits the production of IL-1β induced by LPS in its entirety, as opposed to ITF3056's reduction. Givinostat more than 70% decreased IL-1β secretion at 25, 50, and 100 nM. In PBMCs stimulated with TLR agonists, as well as in combination with IL-12 and IL-18, glinostat (ITF-2357) inhibits the production of IL-6. Givinostat at 50 nM causes IL-6 secretion to drop to 50%, but at 100 and 200 nM, there is no reduction[1]. Givinostat (ITF-2357) inhibits JS-1 cell proliferation in a concentration-dependent manner, as demonstrated by the CCK-8 assay. Givinostat treatment at doses greater than 500 nM is linked to a significant reduction in JS-1 cell proliferation (P<0.01). Additionally, there is a significant difference in the cell inhibition rate (P<0.05) between the group that received LPS treatment and the group that received the same concentration of Givinostat cotreated with ≥250 nM plus LPS[2].
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| ln Vivo |
Givinostat (ITF2357) at 10 mg/kg is used as a positive control and, as expected, reduced serum TNFα by 60%. It is remarkable that pretreatment with ITF3056, starting at 0.1 mg/kg, dramatically lowers the level of circulating TNFα by almost 90%. An elevated dose of 10 mg/kg of LPS is injected, and blood is drawn after 4 hours to obtain a notable rise in serum IL-1β production. Similarly, a 22% reduction for 1 mg/kg and a 40% reduction for 5 mg/kg occurs when pretreated with lower doses of Givinostat (ITF-2357)[1].
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| Enzyme Assay |
The procedure for the assay involves mixing the crude cellular extract (5 μL) with 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 check for HDAC inhibition, add 50 μL of ITF2357. After the mixture has been incubated for a full night at room temperature, 50 μL of a solution made of 259 μL 37% HCl, 28 μL acetic acid, and 1 mL distilled water is added to quench the reaction. The organic extraction method is used to separate the [3H]acetyl residues that are released from the substrate. A beta-counter is used to measure radioactivity after adding 200 μL of the organic phase to standard scintillation fluid. By measuring the difference between the radioactivity of the inhibitor-containing samples and the control sample that only contained cellular crude extract, one can determine the concentration of HDACs that inhibits 50% of the control activity.
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| Cell Assay |
Following a 24-hour culture period in DMEM supplemented with 10% fetal bovine serum, 30 wells containing JS-1 cells are split into two groups. Givinostat (ITF-2357) is added to the culture medium in the first group at final concentrations of 0 nM, 125 nM, 250 nM, 500 nM, and 1000 nM. In the second group, 100 nM of LPS solution is added concurrently with Givinostat at appropriate concentrations. For every group, three replicates are carried out. Following a 24-hour inoculation period at 37°C and 5% CO2, 10 μL of CCK-8 solution is incubated in each well (100 μL). A microplate reader is used to measure the absorbance at 450 nm after the plates are incubated for one hour at 37°C[2].
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| Animal Protocol |
Mice: For a minimum of five days prior to usage, C57BL/6 mice are kept in the animal facility. Intraperitoneal injection of ITF3056 and oral administration of Givinostat (ITF2357) at a dose of 10 mg/kg are used in the comparative study. LPS from Salmonella typhimurium is administered intraperitoneally to the animals at a dose of 2.5 mg/kg one hour after the compounds are administered. Serum is collected and kept at -80°C until further examination of cytokine production, and mice are sacrificed 90 minutes after the LPS treatment.
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| References |
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| Molecular Formula |
C24H27N3O4
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| Molecular Weight |
421.49
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| Exact Mass |
421.20
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| Elemental Analysis |
C, 68.39; H, 6.46; N, 9.97; O, 15.18
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| CAS # |
497833-27-9
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| Related CAS # |
Givinostat hydrochloride monohydrate;732302-99-7;Givinostat hydrochloride;199657-29-9
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| Appearance |
Solid powder
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| SMILES |
CCN(CC)CC1=CC2=C(C=C1)C=C(C=C2)COC(=O)NC3=CC=C(C=C3)C(=O)NO
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| InChi Key |
YALNUENQHAQXEA-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C24H27N3O4/c1-3-27(4-2)15-17-5-7-21-14-18(6-8-20(21)13-17)16-31-24(29)25-22-11-9-19(10-12-22)23(28)26-30/h5-14,30H,3-4,15-16H2,1-2H3,(H,25,29)(H,26,28)
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| Chemical Name |
[6-(diethylaminomethyl)naphthalen-2-yl]methyl N-[4-(hydroxycarbamoyl)phenyl]carbamate
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| Synonyms |
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
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| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.3725 mL | 11.8627 mL | 23.7254 mL | |
| 5 mM | 0.4745 mL | 2.3725 mL | 4.7451 mL | |
| 10 mM | 0.2373 mL | 1.1863 mL | 2.3725 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT01761968 | Active Recruiting |
Drug: givinostat | Chronic Myeloproliferative Neoplasms |
Italfarmaco | March 2013 | Phase 2 |
| NCT05933057 | Not yet recruiting | Drug: Givinostat Drug: Placebo |
Duchenne Muscular Dystrophy | Italfarmaco | December 2023 | Phase 3 |
| NCT06093672 | Not yet recruiting | Drug: Givinostat Hydrochloride Drug: Hydroxy Urea |
Polycythemia Vera | Italfarmaco | December 2023 | Phase 3 |
| NCT05860114 | Completed | Drug: Givinostat | Drug Drug Interaction | Italfarmaco | March 21, 2022 | Phase 1 |
| NCT05845567 | Completed | Drug: Givinostat Drug: Clarithromycin |
Drug Drug Interaction | Italfarmaco | March 21, 2022 | Phase 1 |
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