|Chemical and physical data|
|Molar mass||421.489 g/mol|
|3D model (JSmol)|
|(what is this?)|
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 (including for relapsed leukemias and myelomas), and has been granted orphan drug designation in the European Union for the treatment of systemic juvenile idiopathic arthritis, polycythaemia vera. and Duchenne muscular dystrophy.
A preclinical study produced early results suggesting the molecule might help with diastolic dysfunction.
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 JAK2(V617F), 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.
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- National Cancer Institute (2010). "Gavinostat". NCI Cancer Dictionary. U.S. National Institutes of Health. Retrieved 2010-09-15.
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- 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.
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- WO patent application 1997/043251, "Compounds with anti-inflammatory and immunosuppressive activities", published 1997-11-20, assigned to Italfarmaco S.p.A.
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- Amaru Calzada, Ariel; Todoerti, Katia; Donadoni, Luca; Pellicioli, Anna; Tuana, Giacomo; Gatta, Raffaella; Neri, Antonino; Finazzi, Guido; Mantovani, Roberto; Rambaldi, Alessandro; Introna, Martino; Lombardi, Luigia; Golay, Josée (August 2012). "The HDAC inhibitor Givinostat modulates the hematopoietic transcription factors NFE2 and C-MYB in JAK2(V617F) myeloproliferative neoplasm cells". Experimental Hematology. 40: 634–645.e10. doi:10.1016/j.exphem.2012.04.007. PMID 22579713.