Identification

Name
Belinostat
Accession Number
DB05015
Description

Belinostat is a novel agent that inhibits the enzyme histone deacetylase (HDAC) with a sulfonamide-hydroxamide structure. It was developed as an orphan drug to target hematological malignancies and solid tumors by TopoTarget. The safety and efficacy of belinostat is currently being evaluated for use in combination with traditional front-line therapies for the treatment of PTCL. Intravenous administration of the agent is available as Beleodaq as monotherapy and the dosing regimen involves a 21-day cycle. It was US-approved in July 2014 as a therapeutic agent for relapsed or refractory peripheral T-cell lymphoma.

Type
Small Molecule
Groups
Approved, Investigational
Structure
Thumb
Weight
Average: 318.35
Monoisotopic: 318.067428113
Chemical Formula
C15H14N2O4S
Synonyms
  • Belinostat
External IDs
  • PX-105684
  • PXD-101
  • PXD101

Pharmacology

Indication

Belinostat is indicated for the treatment of patients with relapsed or refractory peripheral T-cell lymphoma (PTCL) with manageable safety profile. It is a potential alternative therapy for patients who did not experience adequate response to first-line drugs for PTCL. It can be used in patients with baseline thrombocytopenia 2.

Associated Conditions
Contraindications & Blackbox Warnings
Learn about our commercial Contraindications & Blackbox Warnings data.
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Pharmacodynamics

Beleodaq is a histone deacetylase (HDAC) inhibitor that exhibits pan-HDAC inhibition and potent growth inhibitory and pro-apoptotic activities in a variety of tumor cells, including PTCL cells, at nanomolar concentrations 2. None of the trials show any clinically relevant changes caused by Beleodaq on heart rate, PR duration or QRS duration as measures of autonomic state, atrio-ventricular conduction or depolarization; there were no cases of Torsades de Pointes.

Mechanism of action

Belinostat inhibits the activity of histone deacetylase (HDAC) thus prevents the removal of acetyl groups from the lysine residues of histones and some non-histone proteins. In vitro, belinostat caused the accumulation of acetylated histones and other proteins, increased the expression of tumor-suppressor genes. It ultimately induces cell cycle arrest, inhibition of angiogenesis and/or apoptosis of some transformed cells.

TargetActionsOrganism
AHistone deacetylase
inhibitor
Humans
Absorption
Not Available
Volume of distribution

The volume of distribution is 409 ± 76.7 L.

Protein binding

92.9% and 95.8% of belinostat is bound to protein.

Metabolism

Primarily metabolized by hepatic UGT1A1. Strong UGT1A1 inhibitors are expected to increase exposure to belinostat. Belinostat also undergoes hepatic metabolism by CYP2A6, CYP2C9, and CYP3A4 enzymes to form belinostat amide and belinostat acid. The enzymes responsible for the formation of methyl belinostat and 3-(anilinosulfonyl)-benzenecarboxylic acid, (3-ASBA) are not known

Hover over products below to view reaction partners

Route of elimination

Approximately 40% of the belinostat dose is excreted renally, primarily as metabolites and less than 2% of total dose recovered as unchanged parent drug.

Half-life

Displays a three-compartment pharmacokinetic property with elimination half life of 1.1 hours

Clearance

1240 mL/min

Adverse Effects
Learn about our commercial Adverse Effects data.
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Toxicity

Belinostat is genotoxic according to Ames test and may impair male fertility. Weekly complete blood count should be monitored during treatment to adjust the dosage as intravenous infusion of belinostat is frequently associated with hematologic toxicity such as leukopenia and thrombocytopenia. Incidences of infections such as sepsis, hepatotoxicity, tumor lysis syndrome, gastrointestinal toxicity, and embryo-fetal toxicity may occur. No specific information is available on the treatment of overdosage of Beleodaq. There is no antidote for Beleodaq and it is not known if Beleodaq is dialyzable. If an overdose occurs, general supportive measures should be instituted as deemed necessary by the treating physician.

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Interacting Gene/EnzymeAllele nameGenotype(s)Defining Change(s)Type(s)DescriptionDetails
UDP-glucuronosyltransferase 1-1UGT1A1*28Not Availableextra TA in promoter, homozygousADR Directly StudiedPatients who carry this genotype in UGT1A1 are at greater risk of experiencing dose-limiting toxicity from belinostat therapy.Details
UDP-glucuronosyltransferase 1-1UGT1A1*60(C;C)A > CADR Directly StudiedPatients who carry this genotype in UGT1A1 may be at greater risk of experiencing dose-limiting toxicity from belinostat therapy.Details

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 Belinostat.
AbciximabThe risk or severity of bleeding can be increased when Abciximab is combined with Belinostat.
AcenocoumarolThe metabolism of Acenocoumarol can be increased when combined with Belinostat.
AcetaminophenThe metabolism of Acetaminophen can be increased when combined with Belinostat.
Acetylsalicylic acidThe risk or severity of bleeding can be increased when Acetylsalicylic acid is combined with Belinostat.
AcyclovirThe metabolism of Acyclovir can be increased when combined with Belinostat.
AdalimumabThe risk or severity of adverse effects can be increased when Adalimumab is combined with Belinostat.
AdenineThe metabolism of Belinostat can be decreased when combined with Adenine.
Adenovirus type 7 vaccine liveThe risk or severity of infection can be increased when Adenovirus type 7 vaccine live is combined with Belinostat.
AfatinibThe serum concentration of Belinostat can be increased when it is combined with Afatinib.
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
No interactions found.

Products

Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
BeleodaqInjection, powder, lyophilized, for solution500 mg/10mLIntravenousAcrotech Biopharma Llc2014-07-21Not applicableUS flag
BeleodaqInjection, powder, lyophilized, for solution500 mg/10mLIntravenousSpectrum Pharmaceuticals, Inc.2014-07-21Not 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
L01XX49 — Belinostat
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as cinnamic acids and derivatives. These are organic aromatic compounds containing a benzene and a carboxylic acid group (or a derivative thereof) forming 3-phenylprop-2-enoic acid.
Kingdom
Organic compounds
Super Class
Phenylpropanoids and polyketides
Class
Cinnamic acids and derivatives
Sub Class
Not Available
Direct Parent
Cinnamic acids and derivatives
Alternative Parents
Sulfanilides / Benzenesulfonamides / Benzenesulfonyl compounds / Styrenes / Organosulfonamides / Aminosulfonyl compounds / Hydroxamic acids / Organopnictogen compounds / Organonitrogen compounds / Organic oxides
show 2 more
Substituents
Aminosulfonyl compound / Aromatic homomonocyclic compound / Benzenesulfonamide / Benzenesulfonyl group / Benzenoid / Carbonyl group / Carboxylic acid derivative / Cinnamic acid or derivatives / Hydrocarbon derivative / Hydroxamic acid
show 14 more
Molecular Framework
Aromatic homomonocyclic compounds
External Descriptors
sulfonamide, hydroxamic acid, olefinic compound (CHEBI:61076)

Chemical Identifiers

UNII
F4H96P17NZ
CAS number
866323-14-0
InChI Key
NCNRHFGMJRPRSK-MDZDMXLPSA-N
InChI
InChI=1S/C15H14N2O4S/c18-15(16-19)10-9-12-5-4-8-14(11-12)22(20,21)17-13-6-2-1-3-7-13/h1-11,17,19H,(H,16,18)/b10-9+
IUPAC Name
(2E)-N-hydroxy-3-[3-(phenylsulfamoyl)phenyl]prop-2-enamide
SMILES
ONC(=O)\C=C\C1=CC=CC(=C1)S(=O)(=O)NC1=CC=CC=C1

References

General References
  1. Moskowitz AJ, Horwitz SM: Targeting histone deacetylases in T-cell lymphoma. Leuk Lymphoma. 2017 Jun;58(6):1306-1319. doi: 10.1080/10428194.2016.1247956. Epub 2016 Nov 4. [PubMed:27813438]
  2. Hood K, Shah A: Belinostat for Relapsed or Refractory Peripheral T-Cell Lymphoma. J Adv Pract Oncol. 2016 Mar;7(2):209-218. Epub 2016 Mar 1. [PubMed:28090369]
  3. Wang LZ, Ramirez J, Yeo W, Chan MY, Thuya WL, Lau JY, Wan SC, Wong AL, Zee YK, Lim R, Lee SC, Ho PC, Lee HS, Chan A, Ansher S, Ratain MJ, Goh BC: Glucuronidation by UGT1A1 is the dominant pathway of the metabolic disposition of belinostat in liver cancer patients. PLoS One. 2013;8(1):e54522. doi: 10.1371/journal.pone.0054522. Epub 2013 Jan 30. [PubMed:23382909]
  4. Valiuliene G, Stirblyte I, Cicenaite D, Kaupinis A, Valius M, Navakauskiene R: Belinostat, a potent HDACi, exerts antileukaemic effect in human acute promyelocytic leukaemia cells via chromatin remodelling. J Cell Mol Med. 2015 Jul;19(7):1742-55. doi: 10.1111/jcmm.12550. Epub 2015 Apr 11. [PubMed:25864732]
PubChem Compound
6918638
PubChem Substance
347827703
ChemSpider
5293831
BindingDB
25150
RxNav
1543543
ChEBI
61076
ChEMBL
CHEMBL408513
ZINC
ZINC000003818726
PDBe Ligand
5OG
Wikipedia
Belinostat
PDB Entries
5een
FDA label
Download (308 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
2Active Not RecruitingTreatmentGlioblastoma Multiforme of Brain1
2CompletedTreatmentAdult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities / Adult Acute Myeloid Leukemia With Del(5q) / Adult Acute Myeloid Leukemia With Inv(16)(p13;q22) / Adult Acute Myeloid Leukemia With T(15;17)(q22;q12) / Adult Acute Myeloid Leukemia With T(16;16)(p13;q22) / Adult Acute Myeloid Leukemia With T(8;21)(q22;q22) / Recurrent Adult Acute Myeloid Leukemia / Untreated Adult Acute Myeloid Leukemia1
2CompletedTreatmentAdvanced Malignant Mesothelioma / Epithelial Mesothelioma / Recurrent Malignant Mesothelioma / Sarcomatous Mesothelioma1
2CompletedTreatmentAdvanced thymic carcinoma / Thymic Carcinoma1
2CompletedTreatmentAnaplastic Large Cell Lymphoma / Anaplastic Large-Cell Lymphoma / Recurrent Adult Diffuse Large Cell Lymphoma / Recurrent Mantle Cell Lymphoma1
2CompletedTreatmentBrenner Tumor / Fallopian Tube Cancer / Ovarian Clear Cell Cystadenocarcinoma / Ovarian Endometrioid Adenocarcinoma / Ovarian Mixed Epithelial Carcinoma / Ovarian Mucinous Cystadenocarcinoma / Ovarian Serous Cystadenocarcinoma / Ovarian Undifferentiated Adenocarcinoma / Primary Peritoneal Cavity Cancer / Recurrent Ovarian Epithelial Cancer1
2CompletedTreatmentCarcinoma of Unknown Primary1
2CompletedTreatmentDe Novo Myelodysplastic Syndromes / Previously Treated Myelodysplastic Syndromes / Secondary Myelodysplastic Syndromes1
2CompletedTreatmentFallopian Tube Cancer / Fallopian Tube Carcinoma / Primary Peritoneal Carcinoma / Primary Peritoneal Cavity Cancer / Recurrent Borderline Ovarian Surface Epithelial-stromal Tumor / Recurrent Ovarian Carcinoma / Recurrent Ovarian Epithelial Cancer / Stage III Borderline Ovarian Surface Epithelial-stromal Tumor / Stage III Ovarian Cancer / Stage III Ovarian Epithelial Cancer / Stage IV Borderline Ovarian Surface Epithelial-stromal Tumor / Stage IV Ovarian Cancer / Stage IV Ovarian Epithelial Cancer1
2CompletedTreatmentMultiple Myeloma (MM)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Injection, powder, lyophilized, for solutionIntravenous500 mg/10mL
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US6888027No2005-05-032021-09-27US flag
US8835501No2014-09-162027-10-27US 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
water solubility0.14 mg/mLFDA Label
pKa7.87 and 8.71 by potentiometryFDA LABEL
Predicted Properties
PropertyValueSource
Water Solubility0.0285 mg/mLALOGPS
logP1.83ALOGPS
logP1.81ChemAxon
logS-4ALOGPS
pKa (Strongest Acidic)7.82ChemAxon
pKa (Strongest Basic)-5.1ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count4ChemAxon
Hydrogen Donor Count3ChemAxon
Polar Surface Area95.5 Å2ChemAxon
Rotatable Bond Count4ChemAxon
Refractivity83.48 m3·mol-1ChemAxon
Polarizability30.99 Å3ChemAxon
Number of Rings2ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET Features
Not Available

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

Targets

Kind
Protein group
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...

Components:
References
  1. Hood K, Shah A: Belinostat for Relapsed or Refractory Peripheral T-Cell Lymphoma. J Adv Pract Oncol. 2016 Mar;7(2):209-218. Epub 2016 Mar 1. [PubMed:28090369]
  2. FDA Label [Link]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
General Function
Protein homodimerization activity
Specific Function
UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. This isoform glucuronidates bilirubin IX-alpha to form both the...
Gene Name
UGT1A4
Uniprot ID
P22310
Uniprot Name
UDP-glucuronosyltransferase 1-4
Molecular Weight
60024.535 Da
References
  1. Wang LZ, Ramirez J, Yeo W, Chan MY, Thuya WL, Lau JY, Wan SC, Wong AL, Zee YK, Lim R, Lee SC, Ho PC, Lee HS, Chan A, Ansher S, Ratain MJ, Goh BC: Glucuronidation by UGT1A1 is the dominant pathway of the metabolic disposition of belinostat in liver cancer patients. PLoS One. 2013;8(1):e54522. doi: 10.1371/journal.pone.0054522. Epub 2013 Jan 30. [PubMed:23382909]
  2. Beleodaq (Belinostat) FDA Label [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Steroid hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP2C8
Uniprot ID
P10632
Uniprot Name
Cytochrome P450 2C8
Molecular Weight
55824.275 Da
References
  1. Backman JT, Filppula AM, Niemi M, Neuvonen PJ: Role of Cytochrome P450 2C8 in Drug Metabolism and Interactions. Pharmacol Rev. 2016 Jan;68(1):168-241. doi: 10.1124/pr.115.011411. [PubMed:26721703]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Steroid hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP2C9
Uniprot ID
P11712
Uniprot Name
Cytochrome P450 2C9
Molecular Weight
55627.365 Da
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inducer
General Function
Oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP1A2
Uniprot ID
P05177
Uniprot Name
Cytochrome P450 1A2
Molecular Weight
58293.76 Da
References
  1. Yu J, Ritchie TK, Zhou Z, Ragueneau-Majlessi I: Key Findings from Preclinical and Clinical Drug Interaction Studies Presented in New Drug and Biological License Applications Approved by the Food and Drug Administration in 2014. Drug Metab Dispos. 2016 Jan;44(1):83-101. doi: 10.1124/dmd.115.066720. Epub 2015 Sep 30. [PubMed:26424199]
  2. FDA Cross discipline team leader review [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Xenobiotic-transporting atpase activity
Specific Function
Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
Gene Name
ABCB1
Uniprot ID
P08183
Uniprot Name
Multidrug resistance protein 1
Molecular Weight
141477.255 Da

Drug created on October 21, 2007 16:23 / Updated on July 09, 2020 15:20

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