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Vorinostat

Vorinostat
Systematic (IUPAC) name
N-Hydroxy-N′-phenyloctanediamide
Clinical data
Trade names Zolinza
AHFS/Drugs.com
MedlinePlus
Licence data US FDA:
Pregnancy
category
  • US: D (Evidence of risk)
Legal status
Routes of
administration
Oral
Pharmacokinetic data
Protein binding 71%
Metabolism Hepatic glucuronidation and oxidation
CYP system not involved
Biological half-life 2 hours
Excretion Renal (negligible)
Identifiers
CAS Registry Number  Y
ATC code L01
PubChem CID:
IUPHAR/BPS
DrugBank  Y
ChemSpider  Y
UNII  Y
KEGG  Y
ChEBI  N
ChEMBL  Y
Chemical data
Formula C14H20N2O3
Molecular mass 264.32 g/mol
 N   

Vorinostat (rINN) also known as suberanilohydroxamic acid (suberoyl+anilide+hydroxamic acid abbreviated as SAHA) is a member of a larger class of compounds that inhibit histone deacetylases (HDAC). Histone deacetylase inhibitors (HDI) have a broad spectrum of epigenetic activities.

Vorinostat is marketed under the name Zolinza for the treatment of cutaneous T cell lymphoma (CTCL) when the disease persists, gets worse, or comes back during or after treatment with other medicines.[1] The compound was developed by Columbia University chemist Ronald Breslow and Memorial Sloan-Kettering researcher Paul Marks.[2][3]

Contents

  • Medical uses 1
  • Mechanism of action 2
  • Clinical trials 3
  • Preclinical investigations 4
  • See also 5
  • References 6
  • External links 7

Medical uses

Vorinostat was the first histone deacetylase inhibitor[4] approved by the U.S. Food and Drug Administration (FDA) for the treatment of CTCL on October 6, 2006.[5] It also failed to demonstrate efficacy in treating acute myeloid leukemia in a phase II study.[6]

Mechanism of action

Vorinostat has been shown to bind to the active site of histone deacetylases and act as a chelator for Zinc ions also found in the active site of histone deacetylases [7] Vorinostat's inhibition of histone deacetylases results in the accumulation of acetylated histones and acetylated proteins, including transcription factors crucial for the expression of genes needed to induce cell differentiation.[7]

Clinical trials

Vorinostat has also been used to treat Sézary syndrome, another type of lymphoma closely related to CTCL.[8]

A recent study suggested that vorinostat also possesses some activity against recurrent glioblastoma multiforme, resulting in a median overall survival of 5.7 months (compared to 4 - 4.4 months in earlier studies).[9] Further brain tumor trials are planned in which vorinostat will be combined with other drugs.

Including vorinostat in treatment of advanced non-small-cell lung cancer (NSCLC) showed improved response rates and increased median progression free survival and overall survival (although the survival improvements were not significant at the P=0.05 level).[10]

It has given encouraging results in a phase II trial for myelodysplastic syndromes in combination with Idarubicin and Cytarabine.[11]

Preclinical investigations

Vorinostat is an interesting target for scientists interested in eradicating HIV from infected persons.[12] Vorinostat was recently shown to have both in vitro and in vivo effects against latently HIV infected T-cells.[13][14]

Vorinostat also has shown some activity against the pathophysiological changes in Alpha 1-antitrypsin deficiency[15] and Cystic Fibrosis.[16]

See also

References

  1. ^ "ZOLINZA, Merck's Investigational Medicine for Advanced Cutaneous T-Cell Lymphoma (CTCL), To Receive Priority Review from U.S. Food and Drug Administration" (Press release). Merck & Co. June 7, 2006. Retrieved 2006-10-06. 
  2. ^ Lee JH1, Mahendran A, Yao Y, Ngo L, Venta-Perez G, Choy ML, Kim N, Ham WS, Breslow R, Marks PA. "Development of a histone deacetylase 6 inhibitor and its biological effects." Proc Natl Acad Sci U S A. 2013 Sep 24;110(39):15704-9. doi:10.1073/pnas.1313893110
  3. ^ Marks, P.A., Breslow, R. B., "Dimethyl sulfoxide to vorinostat: development of this histone deacetylase inhibitor as an anticancer drug" Nature Biotechnology, 2007, 25 doi:10.1038/nbt1272
  4. ^ HDAC Inhibitors Base (vorinostat)
  5. ^ "Zolinza (vorinostat) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Retrieved 16 February 2014. 
  6. ^ Schaefer, EW; Loaiza-Bonilla, A; Juckett, M; DiPersio, JF; Roy, V; Slack, J; Wu, W; Laumann, K; Espinoza-Delgado, I; Gore, SD; Mayo P2C Phase II, Consortium (October 2009). "A phase 2 study of vorinostat in acute myeloid leukemia." (PDF). Haematologica 94 (10): 1375–82.  
  7. ^ a b Richon, Victoria. "Cancer biology: mechanism of antitumour action of vorinostat (suberoylanilide hydroxamic acid), a novel histone deacetylase inhibitor". British Journal of Cancer. Retrieved 3 May 2012. 
  8. ^ Cuneo A, Castoldi. "Mycosis fungoides/Sezary's syndrome". Retrieved 2008-02-15. 
  9. ^ "Vorinostat shows anti-cancer activity in recurrent gliomas" (Press release). Mayo Clinic. June 3, 2007. Retrieved 2007-06-03. 
  10. ^ http://www.rtmagazine.com/reuters_article.asp?id=20091209clin013.html Dec 2009. URL dead Jan 2012
  11. ^ "Zolinza, Idarubicin, Cytarabine Combination Yields High Response Rates In MDS Patients (ASH 2011)". 
  12. ^ "Study of the Effect of Vorinostat on HIV RNA Expression in the Resting CD4+ T Cells of HIV+ Pts on Stable ART". ClinicalTrials.gov. 2011-03-21. 
  13. ^ Archin NM, Espeseth A, Parker D, Cheema M, Hazuda D, Margolis DM (2009). "Expression of latent HIV induced by the potent HDAC inhibitor suberoylanilide hydroxamic acid.". AIDS Res Hum Retroviruses 25 (2): 207–12.  
  14. ^ Contreras X, Schweneker M, Chen CS, McCune JM, Deeks SG, Martin J, et al. (2009). "Suberoylanilide hydroxamic acid reactivates HIV from latently infected cells.". J Biol Chem 284 (11): 6782–9.  
  15. ^ "Histone Deacetylase Inhibitor (HDACi) Suberoylanilide Hydroxamic Acid (SAHA)-mediated Correction of α1-Antitrypsin Deficiency". 2012-09-20. 
  16. ^ "Reduced Histone Deacetylase 7 Activity Restores Function to Misfolded CFTR in Cystic Fibrosis". 2009-12-06. 

External links

  • Vorinostat bound to proteins in the PDB
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