Biology:Givinostat
 | |
| Clinical data | |
|---|---|
| ATC code | |
| Identifiers | |
| |
| CAS Number | |
| PubChem CID | |
| IUPHAR/BPS | |
| ChemSpider | |
| UNII | |
| KEGG | |
| Chemical and physical data | |
| Formula | C24H27N3O4 |
| Molar mass | 421.497 g·mol−1 |
| 3D model (JSmol) | |
| |
| |
  (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 hydroxamic acid 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] polycythaemia vera.[5] and Duchenne muscular dystrophy.
A preclinical study produced early results suggesting the molecule might help with diastolic dysfunction.[6]
ITF2357 was discovered at Italfarmaco of Milan, Italy. It was patented in 1997 and first described in the scientific literature in 2005.[7][8]
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.[9]
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.[8]
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.[10][11] 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
- ↑ "International Nonproprietary Names for Pharmaceutical Substances (INN). Recommended INN: List 63". WHO Drug Information 24 (1): 58–9. 2010. https://www.who.int/medicines/publications/druginformation/innlists/RL63.pdf.
- ↑ National Cancer Institute (2010). "Gavinostat". NCI Cancer Dictionary. U.S. National Institutes of Health. Retrieved 2010-09-15.
- ↑ "Search results for ITF2357". ClinicalTrials.gov. http://clinicaltrials.gov/ct2/results?term=ITF2357.
- ↑ 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". European Medicines Agency. http://www.ema.europa.eu/docs/en_GB/document_library/Orphan_designation/2010/02/WC500074739.pdf.
- ↑ 5.0 5.1 Committee for Orphan Medicinal Products (3 March 2010). "Public summary of opinion on orphan designation: Givinostat for the treatment of polycythaemia vera". European Medicines Agency. http://www.ema.europa.eu/docs/en_GB/document_library/Orphan_designation/2010/03/WC500075167.pdf.
- ↑ "Potential treatment for diastolic dysfunction in heart failure" (in en). ScienceDaily. https://www.sciencedaily.com/releases/2018/02/180207164033.htm.
- ↑ "Compounds with anti-inflammatory and immunosuppressive activities" WO patent 9743251, published 20 November 1997, assigned to Italfarmaco S.p.A.
- ↑ 8.0 8.1 "The histone deacetylase inhibitor ITF2357 reduces production of pro-inflammatory cytokines in vitro and systemic inflammation in vivo". Molecular Medicine 11 (1–12): 1–15. 2005. doi:10.2119/2006-00005.Dinarello. PMID 16557334.
- ↑ "Novel histone deacetylase inhibitors in clinical trials as anti-cancer agents". Journal of Hematology & Oncology 3: 5. February 2010. doi:10.1186/1756-8722-3-5. PMID 20132536.
- ↑ "Treatment options for essential thrombocythemia and polycythemia vera". Expert Review of Hematology 2 (1): 41–55. February 2009. doi:10.1586/17474086.2.1.41. PMID 21082994. http://www.medscape.com/viewarticle/589735.
- ↑ "The histone deacetylase inhibitor ITF2357 selectively targets cells bearing mutated JAK2(V617F)". Leukemia 22 (4): 740–7. April 2008. doi:10.1038/sj.leu.2405049. PMID 18079739.
Further reading
- "Idiopathic juvenile-onset systemic arthritis". Orphanet. January 2007. Orphan number: ORPHA85414. http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=85414.
- "The HDAC inhibitor Givinostat modulates the hematopoietic transcription factors NFE2 and C-MYB in JAK2(V617F) myeloproliferative neoplasm cells". Experimental Hematology 40 (8): 634–45.e10. August 2012. doi:10.1016/j.exphem.2012.04.007. PMID 22579713.
 |  |
