A4093-5mg | ITF2357 (Givinostat) [732302-99-7] Clinisciences

Background

ITF2357, also known as givinostat, is a potent inhibitor of both class I and class II histone deacetylase (HDAC) as well as a potent inhibitor of hematopoietic colony formation by JAKE^V617F-bearing progenitor cells from chronic myeloproliferative neoplasms in vitro. Previous studies has shown that ITF2357 induces apoptosis of multiple myeloma (MM) and acute myelogenous leukemia (AML) cells following induction of p21 and down-modulation of Bcl-2 and Mcl-1 proteins and inhibits the production of pro-inflammatory cytokines (such as IL-1, IL-6, tumor necrosis factor (TNF)-α and interferon (IFN)-γ) by peripheral blood mononuclear cells as well as the production of IL-6 and vascular endothelium growth factor (VEGF) by mesenchymal stromal cells.

Reference

Katia Todoerti, Valentina Barbui, Olga Pedrini, Marta Linett, Gianluca Fossati, Paolo Mascagni, Alessandro Rambaldi, Antonino Neri, Martino Introna, Luigia Lombardi, and Josee Golay. Pleiotropi anti-myeloma activity of ITF2357: inhibition of interleukin-6 receptor signaling and repression of miR-19a and miR-19b. Haematologica 2010; 95(2): 260-269

Product Citation

1. Topper MJ, Vaz M, et al. "Epigenetic Therapy Ties MYC Depletion to Reversing Immune Evasion and Treating Lung Cancer." Cell. 2017 Nov 30;171(6):1284-1300.e21. PMID:29195073
2. Bagnall NH, Hines BM, et al. "Insecticidal activities of histone deacetylase inhibitors against a dipteran parasite of sheep, Lucilia cuprina." Int J Parasitol Drugs Drug Resist. 2017 Apr;7(1):51-60. PMID:28110187

Chemical Properties

Physical Appearance	A solid
Storage	Store at -20°C
M.Wt	475.97
Cas No.	732302-99-7
Formula	C₂₄H₂₇N₃O₄·HCl·H₂O
Synonyms	ITF-2357
Solubility	≥23.8 mg/mL in DMSO; insoluble in EtOH; ≥2.9 mg/mL in H2O with gentle warming and ultrasonic
Chemical Name	(6-((diethylamino)methyl)naphthalen-2-yl)methyl (4-(hydroxycarbamoyl)phenyl)carbamate hydrochloride hydrate
SDF	Download SDF
Canonical SMILES	CCN(CC)CC1=CC2=C(C=C(COC(NC3=CC=C(C(NO)=O)C=C3)=O)C=C2)C=C1.O.Cl
Shipping Condition	Small Molecules with Blue Ice, Modified Nucleotides with Dry Ice.
General tips	We do not recommend long-term storage for the solution, please use it up soon.

Protocol

Cell experiment: [1]
Cell lines	PBMC cells
Preparation method	The solubility of this compound in DMSO is >10 mM. General tips for obtaining a higher concentration: Please warm the tube at 37 °C for 10 minutes and/or shake it in the ultrasonic bath for a while.Stock solution can be stored below -20°C for several months.
Reaction Conditions	100 nM, 24 hours for hyperacetylation
Applications	To test the acetylation ability of ITF2357, rested PBMCs were preincubated with the inhibitor for 1 h at 37° C and then stimulated with LPS. After 3, 6, and 24 h, extracts of the cell pellets were made and the acetylated lysines were determined in total cellular extracts. After 3 h of incubation with LPS in the presence of ITF2357, hyperacetylation is clearly present. However, a greater duration of hyperacetylation up to 24 h was observed in cells exposed to ITF2357.
Animal experiment: [1]
Animal models	BALB/C and C57BL/6 mice
Dosage form	Gavage, 5 mg/kg (BALB/C mice) Gavage, 1 or 10 mg/kg (C57BL/6 mice)
Applications	Mice were given 100 µL water or ITF2357 (5 mg/kg) by gavage and, after 1 h, injected intravenously with 200 µg/mouse of ConA. Mice were bled 24 h later for evaluation of serum ALT levels. ITF2357 pretreatment reduced more than 80% of the ALT levels. A dose of 1 mg/kg ITF2357 was as effective as a dose of 10 mg/kg in reducing ConA hepatitis as measured by ALT levels.
Other notes	Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal.
References: [1] Leoni F, Fossati G, Lewis E C, et al. The histone deacetylase inhibitor ITF2357 reduces production of pro-inflammatory cytokines in vitro and systemic inflammation in vivo. Molecular Medicine, 2005, 11(1-12): 1.

Biological Activity

Description	Givinostat (ITF2357) is a potent inhibitor of HDAC for maize HD2, HD1B and HD1A with IC50 of 10 nM, 7.5 nM and 16 nM, respectively.
Targets	HDAC
IC50	7.5 to 16 nM