|Systematic (IUPAC) name|
|Metabolism||Hepatic glucuronidation and β-oxidation
CYP system not involved
|Metabolites||vorinostat O-glucuronide, 4-anilino-4-oxobutanoic acid (both inactive)|
|Biological half-life||~2 hours (vorinostat and O-glucuronide), 11 hours (4-anilino-4-oxobutanoic acid)|
|ATC code||L01XX38 (WHO)|
|Molar mass||264.32 g/mol|
|(what is this?)|
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 (zo-LINZ-ah) by Merck for the treatment of cutaneous manifestations in patients with cutaneous T cell lymphoma (CTCL) when the disease persists, gets worse, or comes back during or after two systemic therapies. The compound was developed by Columbia University chemist Ronald Breslow and Memorial Sloan-Kettering researcher Paul Marks.
Vorinostat was the first histone deacetylase inhibitor approved by the U.S. Food and Drug Administration (FDA) for the treatment of CTCL on October 6, 2006. It also failed to demonstrate efficacy in treating acute myeloid leukemia in a phase II study.
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. 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.
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). 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 carcinoma (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).
Vorinostat is an interesting target for scientists interested in eradicating HIV from infected persons. Vorinostat was recently shown to have both in vitro and in vivo effects against latently HIV infected T cells.
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- 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
- HDAC Inhibitors Base (vorinostat)
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- "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.
- 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. doi:10.1089/aid.2008.0191. PMC . PMID 19239360.
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- "Histone Deacetylase Inhibitor (HDACi) Suberoylanilide Hydroxamic Acid (SAHA)-mediated Correction of α1-Antitrypsin Deficiency". 2012-09-20.
- "Reduced Histone Deacetylase 7 Activity Restores Function to Misfolded CFTR in Cystic Fibrosis". 2009-12-06.