Vorinostat

Identification

Summary

Vorinostat is a histone deacetylase (HDAC) inhibitor used for the treatment of cutaneous manifestations in patients with progressive, persistent, or recurrent cutaneous T- cell lymphoma (CTCL) following prior systemic therapies.

Brand Names
Zolinza
Generic Name
Vorinostat
DrugBank Accession Number
DB02546
Background

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
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.

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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Management ofPersistent cutaneous t-cell lymphoma••••••••••••
Management ofProgressive cutaneous t-cell lymphoma••••••••••••
Management ofRecurrent cutaneous t-cell lymphoma••••••••••••
Contraindications & Blackbox Warnings
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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)
UHistone deacetylase
inhibitor
Humans
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
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Toxicity

Not Available

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.
AcenocoumarolVorinostat may increase the anticoagulant activities of Acenocoumarol.
AcetohexamideThe therapeutic efficacy of Acetohexamide can be decreased when used in combination with Vorinostat.
Food Interactions
  • Take with food.

Products

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Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
ZolinzaCapsule100 mgOralMerck Ltd.2009-06-29Not applicableCanada flag
ZolinzaCapsule100 mg/1OralMerck Sharp & Dohme Llc2006-10-06Not applicableUS flag

Categories

ATC Codes
L01XH01 — 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)
Affected organisms
  • Humans and other mammals

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. [Article]
  2. Vorinostat FDA Label [Link]
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
PDB Entries
1c3s / 1t69 / 1zz1 / 3c0z / 4bz6 / 4lxz / 4qa0 / 4qa2 / 4r7l / 5eei
show 4 more

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3CompletedTreatmentAcute Myeloid Leukemia / Untreated Adult Acute Myeloid Leukemia1
3CompletedTreatmentCutaneous T-Cell Lymphoma (CTCL)1
3CompletedTreatmentLung Cancer / Mesothelioma1
3CompletedTreatmentMultiple Myeloma (MM)1
3Unknown StatusTreatmentMultiple Myeloma (MM)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
  • Merck & Co.
  • Patheon Inc.
Dosage Forms
FormRouteStrength
CapsuleOral100 mg
CapsuleOral100 mg/1
CapsuleOral100.000 mg
Capsule, coatedOral100 mg
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

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-MSsplash10-006x-4920000000-0b60d0a81534425ab7be
LC-MS/MS Spectrum - LC-ESI-Hybrid FT , PositiveLC-MS/MSsplash10-0udi-0859000000-0a83404097a3e01eb158
MS/MS Spectrum - , positiveLC-MS/MSsplash10-001l-9750000000-d26ffebbce9b1bc73b92
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSsplash10-02ai-5980000000-b0ee9ea4fa4443b6b594
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSsplash10-03e9-0390000000-b1c9d1f157518356c8de
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSsplash10-03yi-9550000000-7f907fa93a26d1a24c5a
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSsplash10-06rx-8290000000-7abe5eccefddbc941ff2
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSsplash10-052f-9210000000-29c9687bef325d87c0d8
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSsplash10-00ls-9410000000-baf1623b6a94770cf257
Predicted 1H NMR Spectrum1D NMRNot Applicable
Predicted 13C NMR Spectrum1D NMRNot Applicable
Chromatographic Properties
Collision Cross Sections (CCS)
AdductCCS Value (Å2)Source typeSource
[M-H]-178.1972662
predicted
DarkChem Lite v0.1.0
[M-H]-178.6766662
predicted
DarkChem Lite v0.1.0
[M-H]-162.11702
predicted
DeepCCS 1.0 (2019)
[M+H]+179.5752662
predicted
DarkChem Lite v0.1.0
[M+H]+180.3169662
predicted
DarkChem Lite v0.1.0
[M+H]+164.47502
predicted
DeepCCS 1.0 (2019)
[M+Na]+178.3458662
predicted
DarkChem Lite v0.1.0
[M+Na]+178.5241662
predicted
DarkChem Lite v0.1.0
[M+Na]+170.56816
predicted
DeepCCS 1.0 (2019)

Targets

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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. [Article]
  2. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [Article]
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. [Article]
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. [Article]
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. [Article]
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
Kind
Protein group
Organism
Humans
Pharmacological action
Unknown
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...

Components:
References
  1. Wang ZT, Chen ZJ, Jiang GM, Wu YM, Liu T, Yi YM, Zeng J, Du J, Wang HS: Histone deacetylase inhibitors suppress mutant p53 transcription via HDAC8/YY1 signals in triple negative breast cancer cells. Cell Signal. 2016 May;28(5):506-515. doi: 10.1016/j.cellsig.2016.02.006. Epub 2016 Feb 11. [Article]
  2. Mates JM, de Silva S, Lustberg M, Van Deusen K, Baiocchi RA, Wu L, Kwiek JJ: A Novel Histone Deacetylase Inhibitor, AR-42, Reactivates HIV-1 from Chronically and Latently Infected CD4(+) T-cells. Retrovirology (Auckl). 2015;7:1-5. doi: 10.4137/RRT.S31632. Epub 2015 Oct 15. [Article]
  3. Kouraklis G, Theocharis S: Histone deacetylase inhibitors: a novel target of anticancer therapy (review). Oncol Rep. 2006 Feb;15(2):489-94. [Article]
  4. Kouraklis G, Theocharis S: Histone deacetylase inhibitors and anticancer therapy. Curr Med Chem Anticancer Agents. 2002 Jul;2(4):477-84. doi: 10.2174/1568011023353921. [Article]
  5. Giuliano M, Pellerito C, Celesia A, Fiore T, Emanuele S: Tributyltin(IV) Butyrate: A Novel Epigenetic Modifier with ER Stress- and Apoptosis-Inducing Properties in Colon Cancer Cells. Molecules. 2021 Aug 19;26(16). pii: molecules26165010. doi: 10.3390/molecules26165010. [Article]
  6. Jaime-Ramirez AC, Yu JG, Caserta E, Yoo JY, Zhang J, Lee TJ, Hofmeister C, Lee JH, Kumar B, Pan Q, Kumar P, Baiocchi R, Teknos T, Pichiorri F, Kaur B, Old M: Reolysin and Histone Deacetylase Inhibition in the Treatment of Head and Neck Squamous Cell Carcinoma. Mol Ther Oncolytics. 2017 May 10;5:87-96. doi: 10.1016/j.omto.2017.05.002. eCollection 2017 Jun 16. [Article]

Drug created at June 13, 2005 13:24 / Updated at March 18, 2024 16:48