VORINOSTAT

Details

Stereochemistry	ACHIRAL
Molecular Formula	C14H20N2O3
Molecular Weight	264.3202
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

SMILES

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

InChI

InChIKey=WAEXFXRVDQXREF-UHFFFAOYSA-N

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)

HIDE SMILES / InChI

Molecular Formula	C14H20N2O3
Molecular Weight	264.3202
Charge	0
Count	MOL RATIO 1 MOL RATIO (average)

Stereochemistry	ACHIRAL
Additional Stereochemistry	No
Defined Stereocenters	0 / 0
E/Z Centers	0
Optical Activity	NONE

Description

Vorinostat (rINN) or suberoylanilide hydroxamic acid (SAHA), is a drug currently under investigation for the treatment of cutaneous T cell lymphoma (CTCL). 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. Vorinostat is used 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. Vorinostat is marketed under the name Zolinza 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.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Potency
Plasmodium falciparum 3D7 7	Inhibitor 8,297	0.12 µM [IC50]
NCI-H661 1	Inhibitor 8,297	0.13 µM [IC50]
Histone deacetylase 1 51	Inhibitor 8,297	0.15 µM [IC50]
Histone deacetylase 2 37	Inhibitor 8,297	0.28 µM [IC50]
Histone deacetylase 8 17	Inhibitor 8,297	1.68 µM [IC50]
Histone deacetylase 3 35	Inhibitor 8,297	57.0 nM [IC50]
Histone deacetylase 6 27	Inhibitor 8,297	1.0 µM [EC50]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Cutaneous T-cell lymphoma 9	Primary		Approved 8,429	Zolinza

C_max

Value	Dose	Analyte	Population
1.2 μM	400 mg single, oral	VORINOSTAT plasma	Homo sapiens
0.83 uM	400 mg single, oral	VORINOSTAT plasma	Homo sapiens
1.17 uM	400 mg 1 times / day steady, oral	VORINOSTAT plasma	Homo sapiens

AUC

Value	Dose	Analyte	Population
5.5 μM × h	400 mg single, oral	VORINOSTAT plasma	Homo sapiens
4.59 uM*h	400 mg single, oral	VORINOSTAT plasma	Homo sapiens
5.59 uM*h	400 mg 1 times / day steady, oral	VORINOSTAT plasma	Homo sapiens

T_1/2

Value	Dose	Analyte	Population
2 h	400 mg single, oral	VORINOSTAT plasma	Homo sapiens
1.94 h	400 mg single, oral	VORINOSTAT plasma	Homo sapiens
2.3 h	400 mg 1 times / day steady, oral	VORINOSTAT plasma	Homo sapiens

F_unbound

Value	Dose	Co-administered	Analyte	Population
29%	400 mg single, oral		VORINOSTAT plasma	Homo sapiens

Doses

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Dose	Population	Adverse events
250 mg 2 times / day multiple, oral	unhealthy, 63 years (range: 38 - 74 years) n = 5	DLT: Fatigue...
300 mg 2 times / day multiple, oral (starting) Highest studied dose	unhealthy, 69 years (range: 26.0 - 80.0 years) n = 12	Disc. AE: Thrombocytopenia, Anemia... Other AEs: Hypotension, Sepsis...

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AEs

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AE	Significance	Dose	Population
Fatigue	grade 3, 1 patient DLT, Disc. AE	250 mg 2 times / day multiple, oral	unhealthy, 63 years (range: 38 - 74 years) n = 5
Diarrhea	11%	300 mg 2 times / day multiple, oral (starting) Highest studied dose	unhealthy, 69 years (range: 26.0 - 80.0 years) n = 12
Dysgeusia	11%	300 mg 2 times / day multiple, oral (starting) Highest studied dose	unhealthy, 69 years (range: 26.0 - 80.0 years) n = 12
Vomiting	11%	300 mg 2 times / day multiple, oral (starting) Highest studied dose	unhealthy, 69 years (range: 26.0 - 80.0 years) n = 12
Anorexia	3%	300 mg 2 times / day multiple, oral (starting) Highest studied dose	unhealthy, 69 years (range: 26.0 - 80.0 years) n = 12

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Overview

CYP3A4	CYP2C9	CYP2D6	hERG
inhibitor 1,587 inducer 781 supressor 21	inhibitor 1,767 inducer 389	inhibitor 1,852	inhibitor 1,612

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP 111 P-gp 1,461 CYP1A2 1,524 CYP2B6 810 CYP2C8 911 CYP2C19 1,478	CYP 270 P-gp 1,537 UGT1A1 418 UGT1A3 422 UGT1A7 236 UGT1A8 283 UGT1A9 380 UGT2B7 389 UGT2B17 213	CYP1A2 701 CYP2B6 547 CYP2C19 293

Drug as perpetrator

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Target	Modality	Activity	Clinical evidence
P-gp 1,650	inhibitor 3,277	inconclusive	no (co-administration study)
CYP2C19 1,553	inhibitor 3,277	no [IC50 79.8 uM]
CYP1A2 1,692	inhibitor 3,277	no [IC50 >100 uM]
CYP2B6 1,001	inhibitor 3,277	no [IC50 >100 uM]
CYP2C8 965	inhibitor 3,277	no [IC50 >100 uM]

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Drug as victim

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Target	Modality	Activity
P-gp 1,537	substrate 3,367	inconclusive
CYP 270	substrate 3,367	no
UGT1A1 418	substrate 3,367	yes
UGT1A3 422	substrate 3,367	yes
UGT1A7 236	substrate 3,367	yes

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Tox targets

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Target	Modality	Activity	Metabolite	Clinical evidence
hERG 1,647	inhibitor 1,626

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Sourcing

Sourcing

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Vendor/Aggregator	ID	URL
ChEBI	CHEBI:45716	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:45716
ChemicalBook	CB3506806	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB3506806
MolPort	MolPort-003-850-293	https://www.molport.com/shop/molecule-link/MolPort-003-850-293
Selleck Chemicals	Vorinostat-(SAHA)	http://www.selleckchem.com/products/Vorinostat-(SAHA).html
ZINC	ZINC000001543873	http://zinc15.docking.org/substances/ZINC000001543873

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PubMed

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Title	Date	PubMed
Induction of apoptosis in U937 human leukemia cells by suberoylanilide hydroxamic acid (SAHA) proceeds through pathways that are regulated by Bcl-2/Bcl-XL, c-Jun, and p21CIP1, but independent of p53.	1999 Nov 25	10597302
Activation of the p21WAF1/CIP1 promoter independent of p53 by the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) through the Sp1 sites.	2000 Nov 23	11126357
Mechanisms of suberoylanilide hydroxamic acid inhibition of mammary cell growth.	2001	11250759
Inhibitors of histone deacetylase are potentially effective anticancer agents.	2001 Apr	11309319
The histone deacetylase inhibitor suberoylanilide hydroxamic acid induces differentiation of human breast cancer cells.	2001 Dec 1	11731433

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Patents

Sample Use Guides

In Vivo Use Guide

400 mg orally once daily with food. If patient is intolerant to therapy, the dose may be reduced to 300 mg orally once daily with food. If necessary, the dose may be further reduced to 300 mg once daily with food for 5 consecutive days each week.

Route of Administration: Oral

In Vitro Use Guide

Concentrations of vorinostat higher than 0.5 uM significantly inhibited the upregulated gene expression of MMP-1 and MMP-13 induced by IL-1β, whereas 0.1 uM vorinostat showed no obvious effect. Conversely, 0.5 uM vorinostat or higher concentration increased the TIMP-1 expression.

Substance Class	Chemical
Record UNII	58IFB293JI
Record Status	`Validated (UNII)`
Record Version

Show entries

Name

Type

Language

VORINOSTAT

Official Name

English

VORINOSTAT [MI]

Common Name

English

NSC-759852

Code

English

VORINOSTAT [ORANGE BOOK]

Common Name

English

NSC-701852

Code

English

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Classification Tree

Code System

Code

Designated/Withdrawn

FDA ORPHAN DRUG

177203

Other antineoplastic agents

WHO-VATC

QL01XX38

Withdrawn

EU-Orphan Drug

EU/3/11/854

Lymphoma

LIVERTOX

NBK548004

Enzyme Inhibitor

NCI_THESAURUS

C1946

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Code System

Code

Type

Description

ChEMBL

CHEMBL98

PRIMARY

SMS_ID

100000088823

PRIMARY

DRUG CENTRAL

4124

PRIMARY

CAS

149647-78-9

PRIMARY

MERCK INDEX

m11502

PRIMARY

Merck Index

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Related Record

Type

Details


					O037NFL7YQ

HISTONE DEACETYLASE 1

TARGET -> INHIBITOR

Interaction Type:

BINDING

Qualification:

IC50

Amount:

4 NANOMOLAR (average)


					X6HV7Q6XP4

HISTONE DEACETYLASE 6

TARGET -> INHIBITOR

Interaction Type:

BINDING

Qualification:

IC50

Amount:

2.2 NANOMOLAR (average)


					0RFO7VC96N

URIDINE DIPHOSPHATE GLUCURONOSYLTRANSFERASE 1A1

METABOLIC ENZYME -> SUBSTRATE

Amount:


					X6HV7Q6XP4

HISTONE DEACETYLASE 6

TARGET -> INHIBITOR

Comments:

Enzymatic Inhibition

Qualification:

IC50

Amount:

10 NANOMOLAR (average)


					58IFB293JI

VORINOSTAT

EXCRETED UNCHANGED

Interaction Type:

AMOUNT EXCRETED

Qualification:

URINE

Amount:

[<1] % (average)
of the dose

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Related Record

Type

Details


					51V7MJ99D8

N-PHENYLOCTANEDIAMIDE

METABOLITE -> PARENT

Amount:


					5O3JZ9EX86

SUBERANILIC ACID

METABOLITE -> PARENT

Amount:


					286703H3MW

4-AMINOPHENYL SULFATE

METABOLITE -> PARENT

Amount:


					S6002H6J9F

ACETAMINOPHEN SULFATE

METABOLITE -> PARENT

Amount:


					ZL94DX0ZW2

2-AMINOPHENYL SULFATE

METABOLITE -> PARENT

Amount:

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Related Record

Type

Details


					58IFB293JI

VORINOSTAT

ACTIVE MOIETY

Amount:

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Name	Property Type	Amount	Parameters
blood-to-plasma ratio	PHARMACOKINETIC	2 (average)

Tmax	PHARMACOKINETIC	2.5 hours (average)	FED CONDITION HIGH-FAT MEAL

Volume of Distribution	PHARMACOKINETIC	150 LITERS [99 to 201] (average)	INTRAVENOUS ADMINISTRATION DOSE 400 mg (average)

Biological Half-life	PHARMACOKINETIC	2 hours (average)

Tmax	PHARMACOKINETIC	1.5 hours [0.5 to 14] (average)	ORAL ADMINISTRATION 400 mg (average) FASTED CONDITION

SMILES

InChI

CNS Activity

Originator

Approval Year

Targets

Conditions

Cmax

AUC

T1/2

Funbound

Doses

AEs

Overview

OverviewOther

Drug as perpetrator​

Drug as victim

Tox targets

Sourcing

PubMed

Patents

Sample Use Guides

C_max

T_1/2

F_unbound

Drug as perpetrator