Vorinostat: Difference between revisions

Vorinostat
Clinical data
Trade names	Zolinza
AHFS/Drugs.com	Monograph
MedlinePlus	a607050
License data	US FDA: Vorinostat;
Routes of; administration	Oral
ATC code	L01XX38 (WHO) ;
Legal status
Legal status	US: ℞-only;
Pharmacokinetic data
Protein binding	71%
Metabolism	Hepatic glucuronidation and oxidation; CYP system not involved
Elimination half-life	2 hours
Excretion	Renal (negligible)
Identifiers
	IUPAC name N-hydroxy-N'-phenyl-octanediamide;
CAS Number	149647-78-9 ;
PubChem CID	5311;
DrugBank	DB02546 ;
ChemSpider	5120 ;
UNII	58IFB293JI;
KEGG	D06320 ;
ChEMBL	ChEMBL98 ;
CompTox Dashboard (EPA)	DTXSID6041133 ;
ECHA InfoCard	100.207.822
Chemical and physical data
Formula	C14H20N2O3
Molar mass	264.32 g/mol g·mol−1
3D model (JSmol)	Interactive image;
	SMILES O=C(Nc1ccccc1)CCCCCCC(=O)NO;
	InChI InChI=1S/C14H20N2O3/c17-13(15-12-8-4-3-5-9-12)10-6-1-2-7-11-14(18)16-19/h3-5,8-9,19H,1-2,6-7,10-11H2,(H,15,17)(H,16,18) ; Key:WAEXFXRVDQXREF-UHFFFAOYSA-N ;
	(verify)

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Revision as of 01:03, 28 July 2012

Vorinostat (rINN) or suberoyl anilide hydroxamic acid (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]

Approvals and indications

Vorinostat was the first histone deacetylase inhibitor^[2] approved by the U.S. Food and Drug Administration (FDA) for the treatment of CTCL on October 6, 2006. It is manufactured by Patheon, Inc., in Mississauga, Ontario, Canada, for Merck & Co., Inc., White House Station, New Jersey.^[3]

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 ^[4] 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. ^[4]

Clinical trials

Vorinostat has also been used to treat Sézary syndrome, another type of lymphoma closely related to CTCL.^[5]

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).^[6] 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).^[7]

It has given encouraging results in a phase II trial for myelodysplastic syndromes in combination with Idarubicin and Cytarabine.^[8]

Preclinical investigations

Vorinostat is an interesting target for scientists interested in eradicating HIV from infected persons.^[9] Vorinostat was recently shown to have both in vitro and in vivo effects against latently HIV infected T-Cells.^[10]^[11]

References

^ "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.
^ HDAC Inhibitors Base (vorinostat)
^ "FDA Approves New Drug for Skin Cancer, Zolinza" (Press release). Food and Drug Administration. October 6, 2006. Retrieved 2006-10-06.
^ ^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.
^ Cuneo A, Castoldi. "Mycosis fungoides/Sezary's syndrome". Retrieved 2008-02-15.
^ "Vorinostat shows anti-cancer activity in recurrent gliomas" (Press release). Mayo Clinic. June 3, 2007. Retrieved 2007-06-03.
^ http://www.rtmagazine.com/reuters_article.asp?id=20091209clin013.html Dec 2009. URL dead Jan 2012
^ "Zolinza, Idarubicin, Cytarabine Combination Yields High Response Rates In MDS Patients (ASH 2011)".
^ "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 2853863. PMID 19239360.{{cite journal}}: CS1 maint: multiple names: authors list (link)
^ 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. doi:10.1074/jbc.M807898200. PMC 2652322. PMID 19136668. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)

External links

Vorinostat bound to proteins in the PDB

@@ Line 91: / Line 91: @@
 It has given encouraging results in a phase II trial for [[myelodysplastic syndromes]] in combination with [[Idarubicin]] and [[Cytarabine]].<ref>{{cite web |url=http://www.mdsbeacon.com/news/2012/01/11/zolinza-vorinostat-idarubicin-cytarabine-combination-yields-high-response-rates-for-mds-patients-ash-2011/ |title=Zolinza, Idarubicin, Cytarabine Combination Yields High Response Rates In MDS Patients (ASH 2011) }}</ref>
-Vorinostat has been shown to flush out the latent HIV virus.
-http://www.sciencedaily.com/releases/2012/03/120308174710.htm
 ==Preclinical investigations==