DrugBank: Vorinostat (DB02546)

targets (6)

Identification

Name

Vorinostat

Accession Number

DB02546 (EXPT02902)

Type

small molecule

Groups

approved

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 in which vorinostat will be combined with other drugs. [Wikipedia]

Structure

Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure

Synonyms

MK0683
N-hydroxy-n'-phenyloctanediamide
N-hyrdroxy-n'-phenyloctanediamide
SAHA
SHH
Suberanilohydroxamic acid
suberoylanilide hydroxamic acid
vorinostat

Brand names

SAHA
Zolinza

Brand name mixtures

Not Available

Categories

Antineoplastic Agents
Enzyme Inhibitors
Anticarcinogenic Agents

CAS number

149647-78-9

Weight

Average: 264.3202
Monoisotopic: 264.147392516

Chemical Formula

C₁₄H₂₀N₂O₃

InChI Key

InChIKey=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)

Plain Text

IUPAC Name

N-hydroxy-N'-phenyloctanediamide

SMILES

ONC(=O)CCCCCCC(=O)NC1=CC=CC=C1

Plain Text

Mass Spec

Not Available

Taxonomy

Kingdom

Organic

Classes

Acetanilides
Steroids and Steroid Derivatives

Substructures

Hydroxy Compounds
Hydroxamic Acids
Amino Ketones
Benzene and Derivatives
Acetanilides
Carboxylic Acids and Derivatives
Aromatic compounds
Carboxamides and Derivatives
Steroids and Steroid Derivatives
Anilines

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.

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.

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).

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

Toxicity

Not Available

Affected organisms

Humans and other mammals

Pathways

Not Available

Pharmacoeconomics

Manufacturers

Merck and co inc

Packagers

Dosage forms

Form	Route	Strength
Capsule	Oral

Prices

Unit description	Cost	Unit
Zolinza 100 mg capsule	83.11 USD	capsule

Patents

Country	Patent Number	Approved	Expires
United States	7456219	2006-11-14	2026-11-14
United States	6087367	1994-10-04	2011-10-04
Canada	2120619	2006-11-21	2012-10-05

Properties

State

solid

Melting point

Not Available

Experimental Properties

Property	Value	Source
pKa	9.2	Various sources

Predicted Properties

Property	Value	Source
water solubility	7.16e-02 g/l	ALOGPS
logP	1.88	ALOGPS
logP	2.00	ChemAxon Molconvert
logS	-3.57	ALOGPS
pKa	14.20	ChemAxon Molconvert
hydrogen acceptor count	3	ChemAxon Molconvert
hydrogen donor count	3	ChemAxon Molconvert
polar surface area	78.43	ChemAxon Molconvert
rotatable bond count	8	ChemAxon Molconvert
refractivity	73.81	ChemAxon Molconvert
polarizability	28.39	ChemAxon Molconvert

References

Synthesis Reference

Not Available

General Reference

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

External Links

Resource	Link
PubChem Compound	5311
PubChem Substance	46508989
ChemSpider	5120
BindingDB	19149
Therapeutic Targets Database	DAP001082
HET	SHH
Drug Product Database	0
RxList	http://www.rxlist.com/cgi/generic/zolinza.htm
Drugs.com	http://www.drugs.com/cdi/vorinostat.html
Wikipedia	http://en.wikipedia.org/wiki/Vorinostat

ATC Codes

Not Available

AHFS Codes

Not Available

PDB Entries

1T69

FDA label

Not Available

MSDS

Not Available

Interactions

Drug Interactions

Not Available

Food Interactions

Oral administration with a high-fat meal resulted in an increase (33%) in the extent of absorption and a modest decrease in the rate of absorption (T_max delayed 2.5 hours) compared to the fasted state.

Targets
1. Histone deacetylase 1 Pharmacological action: yes Actions: inhibitor 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 important role in transcriptional regulation, cell cycle progression and developmental events. Histone deacetylases act via the formation of large multiprotein complexes Organism class: human UniProt ID: Q13547 Gene: HDAC1 Protein Sequence: FASTA Gene Sequence: FASTA SNPs: SNPJam Report References: Xu WS, Parmigiani RB, Marks PA: Histone deacetylase inhibitors: molecular mechanisms of action. Oncogene. 2007 Aug 13;26(37):5541-52. Pubmed Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed 2. Histone deacetylase 2 Pharmacological action: yes Actions: inhibitor Forms transcriptional repressor complexes by associating with MAD, SIN3, YY1 and N-COR. Interacts in the late S-phase of DNA-replication with DNMT1 in the other transcriptional repressor complex composed of DNMT1, DMAP1, PCNA, CAF1 Organism class: human UniProt ID: Q92769 Gene: HDAC2 Protein Sequence: FASTA Gene Sequence: FASTA SNPs: SNPJam Report References: Xu WS, Parmigiani RB, Marks PA: Histone deacetylase inhibitors: molecular mechanisms of action. Oncogene. 2007 Aug 13;26(37):5541-52. Pubmed 3. Histone deacetylase 3 Pharmacological action: yes Actions: inhibitor 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 important role in transcriptional regulation, cell cycle progression and developmental events. Histone deacetylases act via the formation of large multiprotein complexes. Probably participates in the regulation of transcription through its binding to the zinc-finger transcription factor YY1; increases YY1 repression activity. Required to repress transcription of the POU1F1 transcription factor Organism class: human UniProt ID: O15379 Gene: HDAC3 Protein Sequence: FASTA Gene Sequence: FASTA SNPs: SNPJam Report References: Xu WS, Parmigiani RB, Marks PA: Histone deacetylase inhibitors: molecular mechanisms of action. Oncogene. 2007 Aug 13;26(37):5541-52. Pubmed 4. Histone deacetylase 6 Pharmacological action: yes Actions: inhibitor 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 important role in transcriptional regulation, cell cycle progression and developmental events. Histone deacetylases act via the formation of large multiprotein complexes (By similarity). Plays a central role in microtubule-dependent cell motility via deacetylation of tubulin Organism class: human UniProt ID: Q9UBN7 Gene: HDAC6 Protein Sequence: FASTA Gene Sequence: FASTA SNPs: SNPJam Report References: Xu WS, Parmigiani RB, Marks PA: Histone deacetylase inhibitors: molecular mechanisms of action. Oncogene. 2007 Aug 13;26(37):5541-52. Pubmed 5. Histone deacetylase 8 Pharmacological action: unknown 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 important role in transcriptional regulation, cell cycle progression and developmental events. Histone deacetylases act via the formation of large multiprotein complexes Organism class: human UniProt ID: Q9BY41 Gene: HDAC8 Protein Sequence: FASTA Gene Sequence: FASTA SNPs: SNPJam Report 6. Acetoin utilization protein Pharmacological action: unknown Organism class: bacterial UniProt ID: O67135 Gene: acuC1 Protein Sequence: FASTA Gene Sequence: FASTA SNPs: SNPJam Report

Targets

1. Histone deacetylase 1

Pharmacological action: yes
Actions: inhibitor

Organism class: human
UniProt ID: Q13547 Link_out

Gene: HDAC1 Link_out

Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:

Xu WS, Parmigiani RB, Marks PA: Histone deacetylase inhibitors: molecular mechanisms of action. Oncogene. 2007 Aug 13;26(37):5541-52. Pubmed
Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed

2. Histone deacetylase 2

Pharmacological action: yes
Actions: inhibitor

Forms transcriptional repressor complexes by associating with MAD, SIN3, YY1 and N-COR. Interacts in the late S-phase of DNA-replication with DNMT1 in the other transcriptional repressor complex composed of DNMT1, DMAP1, PCNA, CAF1

Organism class: human
UniProt ID: Q92769 Link_out

Gene: HDAC2 Link_out

Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:

Xu WS, Parmigiani RB, Marks PA: Histone deacetylase inhibitors: molecular mechanisms of action. Oncogene. 2007 Aug 13;26(37):5541-52. Pubmed

3. Histone deacetylase 3

Pharmacological action: yes
Actions: inhibitor

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 important role in transcriptional regulation, cell cycle progression and developmental events. Histone deacetylases act via the formation of large multiprotein complexes. Probably participates in the regulation of transcription through its binding to the zinc-finger transcription factor YY1; increases YY1 repression activity. Required to repress transcription of the POU1F1 transcription factor

Organism class: human
UniProt ID: O15379 Link_out

Gene: HDAC3 Link_out

Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:

Xu WS, Parmigiani RB, Marks PA: Histone deacetylase inhibitors: molecular mechanisms of action. Oncogene. 2007 Aug 13;26(37):5541-52. Pubmed

4. Histone deacetylase 6

Pharmacological action: yes
Actions: inhibitor

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 important role in transcriptional regulation, cell cycle progression and developmental events. Histone deacetylases act via the formation of large multiprotein complexes (By similarity). Plays a central role in microtubule-dependent cell motility via deacetylation of tubulin

Organism class: human
UniProt ID: Q9UBN7 Link_out

Gene: HDAC6 Link_out

Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:

Xu WS, Parmigiani RB, Marks PA: Histone deacetylase inhibitors: molecular mechanisms of action. Oncogene. 2007 Aug 13;26(37):5541-52. Pubmed

5. Histone deacetylase 8

Pharmacological action: unknown

Organism class: human
UniProt ID: Q9BY41 Link_out

Gene: HDAC8 Link_out

Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

6. Acetoin utilization protein

Pharmacological action: unknown
Organism class: bacterial
UniProt ID: O67135 Link_out

Gene: acuC1
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

Comments

Drug created on June 13, 2005 07:24 / Updated on November 10, 2010 14:37

This project is supported by Genome Alberta & Genome Canada, a not-for-profit organization that is leading Canada's national genomics strategy with $600 million in funding from the federal government. This project is also supported in part by GenomeQuest, Inc., an enterprise genomic information company serving the life science community.