Givinostat

Givinostat

File:Givinostat structure.svg
Systematic (IUPAC) name
{6-[(diethylamino)methyl]naphthalen-2-yl}methyl [4-(hydroxycarbamoyl)phenyl]carbamate
Clinical data
Pregnancy category	—
Routes of administration	Oral
Legal status
Legal status	Investigational Orphan status in EU for sJIA
Identifiers
CAS Number	497833-27-9
ATC code	none
Chemical data
Formula	C24H27N3O4
Molar mass	421.489 g/mol[[]]

Givinostat (INN) or gavinostat (originally ITF2357) is a histone deacetylase inhibitor with potential anti-inflammatory, anti-angiogenic, and antineoplastic activities. It is a hydroxamate used in the form of its hydrochloride.

Givinostat is in numerous phase II clinical trials, and has been granted orphan drug designation in the European Union for the treatment of systemic juvenile idiopathic arthritis and polycythaemia vera.

ITF2357 was discovered at Italfarmaco of Milan, Italy. It was patented in 1997 and first described in the scientific literature in 2005.

Adverse effects

In clinical trials of givinostat as a salvage therapy for advanced Hodgkin's lymphoma, the most common adverse reactions were fatigue (seen in 50% of participants), mild diarrhea or abdominal pain (40% of participants), moderate thrombocytopenia (decreased platelet counts, seen in one third of patients), and mild leukopenia (a decrease in white blood cell levels, seen in 30% of patients). One-fifth of patients experienced prolongation of the QT interval, a measure of electrical conduction in the heart, severe enough to warrant temporary suspension of treatment.

Mechanism of action

Givinostat 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.

It 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. In patients with polycythaemia, the reduction of mutant JAK2 concentrations by givinostat is believed to slow down the abnormal growth of erythrocytes and ameliorate the symptoms of the disease.

Further reading

• Job-Deslandre, C (January 2007). "Idiopathic juvenile-onset systemic arthritis". Orphanet. Orphan number: ORPHA85414. de:Givinostat

World Health Organization (2010). "International Nonproprietary Names for Pharmaceutical Substances (INN). Recommended INN: List 63". WHO Drug Information 24 (1): 58–9.

National Cancer Institute (2010). "Gavinostat". NCI Cancer Dictionary. U.S. National Institutes of Health. Retrieved 2010-09-15.

"Search results for ITF2357". ClinicalTrials.gov. 

Committee for Orphan Medicinal Products (23 February 2010). "Public summary of opinion on orphan designation: Givinostat for the treatment of systemic-onset juvenile idiopathic arthritis" (PDF). European Medicines Agency. Retrieved 2010-09-15. 

Committee for Orphan Medicinal Products (3 March 2010). "Public summary of opinion on orphan designation: Givinostat for the treatment of polycythaemia vera" (PDF). European Medicines Agency. 

WO patent application 1997/043251, "Compounds with anti-inflammatory and immunosuppressive activities", published 1997-11-20, assigned to Italfarmaco S.p.A.

Leoni F, Fossati G. (2005). "The histone deacetylase inhibitor ITF2357 reduces production of pro-inflammatory cytokines in vitro and systemic inflammation in vivo". Molecular Medicine 11: 1. doi:10.2119/2006-00005.Dinarello. PMID 16557334.

Tan J, Cang S, Ma Y, Petrillo RL, Liu D (2010). "Novel histone deacetylase inhibitors in clinical trials as anti-cancer agents". Journal of Hematology & Oncology 3: 5. doi:10.1186/1756-8722-3-5. PMID 20132536. Review.

Vannucchi AM, Guglielmelli P, Pieri L, Antonioli E, Bosi A (2009). "Treatment options for essential thrombocythemia and polycythemia vera." Expert Review of Hematology 2 (1): 41–55. doi:10.1586/17474086.2.1.41. Review.

Guerini V, Barbui V, Spinelli O, et al. (April 2008). "The histone deacetylase inhibitor ITF2357 selectively targets cells bearing mutated JAK2(V617F)". Leukemia 22 (4): 740–7. doi:10.1038/sj.leu.2405049. PMID 18079739.