Givinostat

Givinostat
Clinical data
Pregnancy
category
  • —
Routes of
administration		 Oral
ATC code none
Legal status
Legal status
Identifiers
CAS Number 497833-27-9 YesY
PubChem (CID) 9804992
IUPHAR/BPS 7490
ChemSpider 7980752 N
UNII 5P60F84FBH YesY
Chemical and physical data
Formula C24H27N3O4
Molar mass 421.489 g/mol
3D model (Jmol) Interactive image
 NYesY (what is this?)  (verify)

Givinostat (INN[1]) or gavinostat (originally ITF2357) is a histone deacetylase inhibitor with potential anti-inflammatory, anti-angiogenic, and antineoplastic activities.[2] 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),[3] and has been granted orphan drug designation in the European Union for the treatment of systemic juvenile idiopathic arthritis[4] and polycythaemia vera.[5]

ITF2357 was discovered at Italfarmaco of Milan, Italy. It was patented in 1997 and first described in the scientific literature in 2005.[6][7]

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.[8]

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.[7]

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.[9][10] 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.[5]

References

  1. ↑ World Health Organization (2010). "International Nonproprietary Names for Pharmaceutical Substances (INN). Recommended INN: List 63". WHO Drug Information 24 (1): 58–9.
  2. ↑ National Cancer Institute (2010). "Gavinostat". NCI Cancer Dictionary. U.S. National Institutes of Health. Retrieved 2010-09-15.
  3. ↑ "Search results for ITF2357". ClinicalTrials.gov.
  4. ↑ 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.
  5. 1 2 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.
  6. ↑ WO patent application 1997/043251, "Compounds with anti-inflammatory and immunosuppressive activities", published 1997-11-20, assigned to Italfarmaco S.p.A.
  7. 1 2 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.
  8. ↑ 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.
  9. ↑ 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.
  10. ↑ 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.

Further reading


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