Vorinostat

Identification

Name
Vorinostat
Accession Number
DB02546
Description

Vorinostat (rINN) or suberoylanilide hydroxamic acid (SAHA), is a drug currently under investigation for the treatment of cutaneous T cell lymphoma (CTCL), a type of skin cancer, to be used when the disease persists, gets worse, or comes back during or after treatment with other medicines. It is the first in a new class of agents known as histone deacetylase inhibitors. 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 using combinations of vorinostat with other drugs.

Type
Small Molecule
Groups
Approved, Investigational
Structure
Thumb
Weight
Average: 264.3202
Monoisotopic: 264.147392516
Chemical Formula
C14H20N2O3
Synonyms
  • Octanedioic acid hydroxyamide phenylamide
  • SAHA
  • SHH
  • Suberanilohydroxamic acid
  • Suberoylanilide hydroxamic acid
  • Vorinostat
  • Vorinostatum
External IDs
  • MK-0683
  • MK0683

Pharmacology

Indication

For the treatment of cutaneous manifestations in patients with cutaneous T-cell lymphoma who have progressive, persistent or recurrent disease on or following two systemic therapies.

Associated Conditions
Contraindications & Blackbox Warnings
Learn about our commercial Contraindications & Blackbox Warnings data.
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Pharmacodynamics
Not Available
Mechanism of action

Vorinostat inhibits the enzymatic activity of histone deacetylases HDAC1, HDAC2 and HDAC3 (Class I) and HDAC6 (Class II) at nanomolar concentrations (IC50< 86 nM). These enzymes catalyze the removal of acetyl groups from the lysine residues of histones proteins. In some cancer cells, there is an overexpression of HDACs, or an aberrant recruitment of HDACs to oncogenic transcription factors causing hypoacetylation of core nucleosomal histones. By inhibiting histone deacetylase, vorinostat causes the accumulation of acetylated histones and induces cell cycle arrest and/or apoptosis of some transformed cells. The mechanism of the antineoplastic effect of vorinostat has not been fully characterized.

TargetActionsOrganism
AHistone deacetylase 1
inhibitor
Humans
AHistone deacetylase 2
inhibitor
Humans
AHistone deacetylase 3
inhibitor
Humans
AHistone deacetylase 6
inhibitor
Humans
UHistone deacetylase 8Not AvailableHumans
UAcetoin utilization proteinNot AvailableAquifex aeolicus (strain VF5)
Absorption
Not Available
Volume of distribution
Not Available
Protein binding

71%

Metabolism

The major pathways of vorinostat metabolism involve glucuronidation and hydrolysis followed by β-oxidation. Human serum levels of two metabolites, O-glucuronide of vorinostat and 4-anilino-4-oxobutanoic acid were measured. Both metabolites are pharmacologically inactive. Compared to vorinostat, the mean steady state serum exposures in humans of the O-glucuronide of vorinostat and 4-anilino-4-oxobutanoic acid were 4-fold and 13-fold higher, respectively. In vitro studies using human liver microsomes indicate negligible biotransformation by cytochromes P450 (CYP).

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Route of elimination

In vitro studies using human liver microsomes indicate negligible biotransformation by cytochromes P450 (CYP). Vorinostat is eliminated predominantly through metabolism with less than 1% of the dose recovered as unchanged drug in urine, indicating that renal excretion does not play a role in the elimination of vorinostat. However, renal excretion does not play a role in the elimination of vorinostat.

Half-life

2 hours

Clearance
Not Available
Adverse Effects
Learn about our commercial Adverse Effects data.
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Toxicity
Not Available
Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
AbataceptThe risk or severity of adverse effects can be increased when Abatacept is combined with Vorinostat.
AbciximabThe risk or severity of bleeding can be increased when Abciximab is combined with Vorinostat.
AcarboseThe therapeutic efficacy of Acarbose can be decreased when used in combination with Vorinostat.
AcebutololThe risk or severity of QTc prolongation can be increased when Vorinostat is combined with Acebutolol.
AcenocoumarolVorinostat may increase the anticoagulant activities of Acenocoumarol.
AcetohexamideThe therapeutic efficacy of Acetohexamide can be decreased when used in combination with Vorinostat.
Acetylsalicylic acidThe risk or severity of bleeding can be increased when Acetylsalicylic acid is combined with Vorinostat.
AcrivastineThe risk or severity of QTc prolongation can be increased when Vorinostat is combined with Acrivastine.
AdalimumabThe risk or severity of adverse effects can be increased when Adalimumab is combined with Vorinostat.
AdenosineThe risk or severity of QTc prolongation can be increased when Vorinostat is combined with Adenosine.
Additional Data Available
  • Extended Description
    Extended Description

    Extended description of the mechanism of action and particular properties of each drug interaction.

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  • Severity
    Severity

    A severity rating for each drug interaction, from minor to major.

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  • Evidence Level
    Evidence Level

    A rating for the strength of the evidence supporting each drug interaction.

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  • Action
    Action

    An effect category for each drug interaction. Know how this interaction affects the subject drug.

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Food Interactions
  • Take with food.

Products

Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
ZolinzaCapsuleOralMerck Ltd.2009-06-29Not applicableCanada flag
ZolinzaCapsule100 mg/1OralMerck Sharp & Dohme Corp.2006-10-06Not applicableUS flag
Additional Data Available
  • Application Number
    Application Number

    A unique ID assigned by the FDA when a product is submitted for approval by the labeller.

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  • Product Code
    Product Code

    A governmentally-recognized ID which uniquely identifies the product within its regulatory market.

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Categories

ATC Codes
L01XX38 — Vorinostat
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as benzene and substituted derivatives. These are aromatic compounds containing one monocyclic ring system consisting of benzene.
Kingdom
Organic compounds
Super Class
Benzenoids
Class
Benzene and substituted derivatives
Sub Class
Not Available
Direct Parent
Benzene and substituted derivatives
Alternative Parents
Propargyl-type 1,3-dipolar organic compounds / Carboximidic acids / Organopnictogen compounds / Organooxygen compounds / Organonitrogen compounds / Hydrocarbon derivatives
Substituents
Aromatic homomonocyclic compound / Carboximidic acid / Carboximidic acid derivative / Hydrocarbon derivative / Monocyclic benzene moiety / Organic 1,3-dipolar compound / Organic nitrogen compound / Organic oxygen compound / Organonitrogen compound / Organooxygen compound
Molecular Framework
Aromatic homomonocyclic compounds
External Descriptors
dicarboxylic acid diamide, hydroxamic acid (CHEBI:45716)

Chemical Identifiers

UNII
58IFB293JI
CAS number
149647-78-9
InChI Key
WAEXFXRVDQXREF-UHFFFAOYSA-N
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)
IUPAC Name
N-hydroxy-N'-phenyloctanediamide
SMILES
ONC(=O)CCCCCCC(=O)NC1=CC=CC=C1

References

Synthesis Reference

Vinayak G. Gore, Madhukar S. Patil, Rahul A. Bhalerao, Hemant M. Mande, Sandeep G. Mekde, "PROCESS FOR THE PREPARATION OF VORINOSTAT." U.S. Patent US20110263712, issued October 27, 2011.

US20110263712
General References
  1. Munshi A, Tanaka T, Hobbs ML, Tucker SL, Richon VM, Meyn RE: Vorinostat, a histone deacetylase inhibitor, enhances the response of human tumor cells to ionizing radiation through prolongation of gamma-H2AX foci. Mol Cancer Ther. 2006 Aug;5(8):1967-74. [PubMed:16928817]
Human Metabolome Database
HMDB0015568
KEGG Drug
D06320
PubChem Compound
5311
PubChem Substance
46508989
ChemSpider
5120
BindingDB
19149
RxNav
194337
ChEBI
45716
ChEMBL
CHEMBL98
ZINC
ZINC000001543873
Therapeutic Targets Database
DAP001082
PharmGKB
PA164748224
PDBe Ligand
SHH
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Vorinostat
AHFS Codes
  • 10:00.00 — Antineoplastic Agents
PDB Entries
1c3s / 1t69 / 1zz1 / 3c0z / 4bz6 / 4lxz / 4qa0 / 4qa2 / 4r7l / 5eei

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3Active Not RecruitingTreatmentCutaneous T-Cell Lymphoma (CTCL)1
3Active Not RecruitingTreatmentMultiple Myeloma (MM)1
3CompletedTreatmentAcute Myeloid Leukemia (AML) / Untreated Adult Acute Myeloid Leukemia1
3CompletedTreatmentLung Cancers / Mesothelioma1
3CompletedTreatmentMultiple Myeloma (MM)1
3WithdrawnTreatmentMalignant Lymphomas1
2Active Not RecruitingTreatmentAcute Myeloid Leukemia (AML)1
2Active Not RecruitingTreatmentBreast Cancer1
2Active Not RecruitingTreatmentChronic Myelomonocytic Leukemia / Chronic Myelomonocytic Leukemia-1 / Chronic Myelomonocytic Leukemia-2 / Myelodysplastic Syndrome / Myelodysplastic Syndrome With Excess Blasts / Myelodysplastic Syndrome With Excess Blasts-1 / Myelodysplastic Syndrome With Excess Blasts-21
2Active Not RecruitingTreatmentCutaneous T-Cell Lymphoma/Mycosis Fungoides1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
  • Merck & Co.
  • Patheon Inc.
Dosage Forms
FormRouteStrength
CapsuleOral
CapsuleOral100 mg/1
Prices
Unit descriptionCostUnit
Zolinza 100 mg capsule83.11USD capsule
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US6087367No2000-07-112011-10-04US flag
CA2120619No2006-11-212012-10-05Canada flag
US7399787No2008-07-152025-02-09US flag
US7732490No2010-06-082023-03-04US flag
US7851509No2010-12-142024-02-21US flag
US8067472No2011-11-292023-03-04US flag
US8101663No2012-01-242023-03-04US flag
US8450372No2013-05-282028-03-18US flag
US7456219No2008-11-252027-03-11US flag
US8093295No2012-01-102026-05-16US flag
USRE38506No2004-04-202015-07-07US flag
US7652069No2010-01-262023-03-04US flag
Additional Data Available
  • Filed On
    Filed On

    The date on which a patent was filed with the relevant government.

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Properties

State
Solid
Experimental Properties
PropertyValueSource
pKa9.2Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.0716 mg/mLALOGPS
logP1.88ALOGPS
logP2ChemAxon
logS-3.6ALOGPS
pKa (Strongest Acidic)8.91ChemAxon
pKa (Strongest Basic)-3.5ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count3ChemAxon
Hydrogen Donor Count3ChemAxon
Polar Surface Area78.43 Å2ChemAxon
Rotatable Bond Count8ChemAxon
Refractivity73.81 m3·mol-1ChemAxon
Polarizability28.39 Å3ChemAxon
Number of Rings1ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET Features
PropertyValueProbability
Human Intestinal Absorption+0.8458
Blood Brain Barrier+0.9861
Caco-2 permeable-0.8957
P-glycoprotein substrateNon-substrate0.6928
P-glycoprotein inhibitor INon-inhibitor0.8741
P-glycoprotein inhibitor IINon-inhibitor0.9317
Renal organic cation transporterNon-inhibitor0.9169
CYP450 2C9 substrateNon-substrate0.8437
CYP450 2D6 substrateNon-substrate0.8345
CYP450 3A4 substrateNon-substrate0.6536
CYP450 1A2 substrateNon-inhibitor0.824
CYP450 2C9 inhibitorNon-inhibitor0.9084
CYP450 2D6 inhibitorNon-inhibitor0.9204
CYP450 2C19 inhibitorNon-inhibitor0.88
CYP450 3A4 inhibitorNon-inhibitor0.9347
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.9336
Ames testAMES toxic0.7891
CarcinogenicityNon-carcinogens0.7278
BiodegradationNot ready biodegradable0.8297
Rat acute toxicity1.9954 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9603
hERG inhibition (predictor II)Non-inhibitor0.8674
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available
LC-MS/MS Spectrum - LC-ESI-Hybrid FT , PositiveLC-MS/MSNot Available
MS/MS Spectrum - , positiveLC-MS/MSsplash10-001l-9750000000-d26ffebbce9b1bc73b92

Targets

Details
1. Histone deacetylase 1
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Transcription regulatory region sequence-specific dna binding
Specific Function
Responsible for the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4). Histone deacetylation gives a tag for epigenetic repression and plays an impo...
Gene Name
HDAC1
Uniprot ID
Q13547
Uniprot Name
Histone deacetylase 1
Molecular Weight
55102.615 Da
References
  1. Xu WS, Parmigiani RB, Marks PA: Histone deacetylase inhibitors: molecular mechanisms of action. Oncogene. 2007 Aug 13;26(37):5541-52. [PubMed:17694093]
  2. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352]
Details
2. Histone deacetylase 2
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Transcription factor binding
Specific Function
Responsible for the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4). Histone deacetylation gives a tag for epigenetic repression and plays an impo...
Gene Name
HDAC2
Uniprot ID
Q92769
Uniprot Name
Histone deacetylase 2
Molecular Weight
55363.855 Da
References
  1. Xu WS, Parmigiani RB, Marks PA: Histone deacetylase inhibitors: molecular mechanisms of action. Oncogene. 2007 Aug 13;26(37):5541-52. [PubMed:17694093]
Details
3. Histone deacetylase 3
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Transcription factor binding
Specific Function
Responsible for the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4), and some other non-histone substrates. Histone deacetylation gives a tag for ...
Gene Name
HDAC3
Uniprot ID
O15379
Uniprot Name
Histone deacetylase 3
Molecular Weight
48847.385 Da
References
  1. Xu WS, Parmigiani RB, Marks PA: Histone deacetylase inhibitors: molecular mechanisms of action. Oncogene. 2007 Aug 13;26(37):5541-52. [PubMed:17694093]
Details
4. Histone deacetylase 6
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Zinc ion binding
Specific Function
Responsible for the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4). Histone deacetylation gives a tag for epigenetic repression and plays an impo...
Gene Name
HDAC6
Uniprot ID
Q9UBN7
Uniprot Name
Histone deacetylase 6
Molecular Weight
131418.19 Da
References
  1. Xu WS, Parmigiani RB, Marks PA: Histone deacetylase inhibitors: molecular mechanisms of action. Oncogene. 2007 Aug 13;26(37):5541-52. [PubMed:17694093]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
General Function
Transcription factor binding
Specific Function
Responsible for the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4). Histone deacetylation gives a tag for epigenetic repression and plays an impo...
Gene Name
HDAC8
Uniprot ID
Q9BY41
Uniprot Name
Histone deacetylase 8
Molecular Weight
41757.29 Da
Kind
Protein
Organism
Aquifex aeolicus (strain VF5)
Pharmacological action
Unknown
General Function
Metal ion binding
Specific Function
Not Available
Gene Name
acuC1
Uniprot ID
O67135
Uniprot Name
Acetoin utilization protein
Molecular Weight
42662.46 Da

Drug created on June 13, 2005 07:24 / Updated on October 27, 2020 11:13

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