Belinostat
Identification
- Summary
Belinostat is a histone deacetylase (HDAC) inhibitor used for the treatment of patients with relapsed or refractory peripheral T-cell lymphoma (PTCL).
- Brand Names
- Beleodaq
- Generic Name
- Belinostat
- DrugBank Accession Number
- DB05015
- Background
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
- 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.
Reduce drug development failure ratesBuild, train, & validate machine-learning modelswith evidence-based and structured datasets.Build, train, & validate predictive machine-learning models with structured datasets.- Associated Conditions
Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Treatment of Refractory peripheral t-cell lymphoma •••••••••••• Treatment of Relapsed peripheral t-cell lymphoma •••••••••••• - Contraindications & Blackbox Warnings
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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.
Target Actions Organism AHistone deacetylase inhibitorHumans - 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
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- 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
- Improve decision support & research outcomesWith structured adverse effects data, including: blackbox warnings, adverse reactions, warning & precautions, & incidence rates. View sample adverse effects data in our new Data Library!Improve decision support & research outcomes with our structured adverse effects data.
- 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.
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs Browse all" title="About SNP Mediated Effects/ADRs" id="snp-actions-info" class="drug-info-popup" href="javascript:void(0);">
Interacting Gene/Enzyme Allele name Genotype(s) Defining Change(s) Type(s) Description Details UDP-glucuronosyltransferase 1-1 UGT1A1*28 Not Available extra TA in promoter, homozygous ADR Directly Studied Patients who carry this genotype in UGT1A1 are at greater risk of experiencing dose-limiting toxicity from belinostat therapy. Details UDP-glucuronosyltransferase 1-1 UGT1A1*60 (C;C) A > C ADR Directly Studied Patients who carry this genotype in UGT1A1 may be at greater risk of experiencing dose-limiting toxicity from belinostat therapy. Details
Interactions
- Drug Interactions Learn More" title="About Drug Interactions" id="structured-interactions-info" class="drug-info-popup" href="javascript:void(0);">
- 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.
Drug Interaction Integrate drug-drug
interactions in your softwareAbatacept The risk or severity of adverse effects can be increased when Abatacept is combined with Belinostat. Abciximab The risk or severity of bleeding can be increased when Abciximab is combined with Belinostat. Abemaciclib The serum concentration of Abemaciclib can be increased when it is combined with Belinostat. Abrocitinib The serum concentration of Belinostat can be increased when it is combined with Abrocitinib. Acenocoumarol The metabolism of Acenocoumarol can be increased when combined with Belinostat. - Food Interactions
- No interactions found.
Products
- Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.
- Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Beleodaq Injection, powder, lyophilized, for solution 500 mg/10mL Intravenous Acrotech Biopharma Llc 2014-07-21 Not applicable US Beleodaq Injection, powder, lyophilized, for solution 500 mg/10mL Intravenous CENEXI - BLA 2014-07-21 Not applicable US Beleodaq Injection, powder, lyophilized, for solution 500 mg/10mL Intravenous Acrotech Biopharma Inc 2014-07-21 Not applicable US
Categories
- ATC Codes
- L01XH04 — Belinostat
- Drug Categories
- Amides
- Amines
- Antineoplastic Agents
- Antineoplastic and Immunomodulating Agents
- Cancer immunotherapy
- Cytochrome P-450 CYP1A2 Inducers
- Cytochrome P-450 CYP1A2 Inducers (weak)
- Cytochrome P-450 CYP2A6 Substrates
- Cytochrome P-450 CYP2A6 Substrates with a Narrow Therapeutic Index
- Cytochrome P-450 CYP2C8 Inhibitors
- Cytochrome P-450 CYP2C8 Inhibitors (weak)
- Cytochrome P-450 CYP2C9 Inhibitors
- Cytochrome P-450 CYP2C9 Inhibitors (strength unknown)
- Cytochrome P-450 CYP3A Substrates
- Cytochrome P-450 CYP3A4 Substrates
- Cytochrome P-450 CYP3A4 Substrates with a Narrow Therapeutic Index
- Cytochrome P-450 Enzyme Inducers
- Cytochrome P-450 Enzyme Inhibitors
- Cytochrome P-450 Substrates
- Enzyme Inhibitors
- Histone deacetylase (HDAC) inhibitors
- Histone Deacetylase Inhibitors
- Hydroxy Acids
- Hydroxylamines
- Immunosuppressive Agents
- Immunotherapy
- Myelosuppressive Agents
- Narrow Therapeutic Index Drugs
- P-glycoprotein substrates
- P-glycoprotein substrates with a Narrow Therapeutic Index
- Sulfones
- Sulfur Compounds
- UGT1A1 Substrates
- UGT1A1 Substrates with a Narrow Therapeutic Index
- 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)
- Affected organisms
- Humans and other mammals
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
- 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. [Article]
- 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. [Article]
- 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. [Article]
- 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. [Article]
- External Links
- PubChem Compound
- 6918638
- PubChem Substance
- 347827703
- ChemSpider
- 5293831
- BindingDB
- 25150
- 1543543
- ChEBI
- 61076
- ChEMBL
- CHEMBL408513
- ZINC
- ZINC000003818726
- PDBe Ligand
- 5OG
- Wikipedia
- Belinostat
- PDB Entries
- 5een
- FDA label
- Download (308 KB)
Clinical Trials
- Clinical Trials Learn More" title="About Clinical Trials" id="clinical-trials-info" class="drug-info-popup" href="javascript:void(0);">
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Injection, powder, lyophilized, for solution Intravenous 500 mg/10mL - Prices
- Not Available
- Patents
Patent Number Pediatric Extension Approved Expires (estimated) Region US6888027 No 2005-05-03 2021-09-27 US US8835501 No 2014-09-16 2027-10-27 US
Properties
- State
- Solid
- Experimental Properties
Property Value Source water solubility 0.14 mg/mL FDA Label pKa 7.87 and 8.71 by potentiometry FDA LABEL - Predicted Properties
Property Value Source Water Solubility 0.0285 mg/mL ALOGPS logP 1.83 ALOGPS logP 1.81 Chemaxon logS -4 ALOGPS pKa (Strongest Acidic) 7.82 Chemaxon pKa (Strongest Basic) -5.1 Chemaxon Physiological Charge 0 Chemaxon Hydrogen Acceptor Count 4 Chemaxon Hydrogen Donor Count 3 Chemaxon Polar Surface Area 95.5 Å2 Chemaxon Rotatable Bond Count 4 Chemaxon Refractivity 83.48 m3·mol-1 Chemaxon Polarizability 30.99 Å3 Chemaxon Number of Rings 2 Chemaxon Bioavailability 1 Chemaxon Rule of Five Yes Chemaxon Ghose Filter Yes Chemaxon Veber's Rule No Chemaxon MDDR-like Rule No Chemaxon - Predicted ADMET Features
- Not Available
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
- Chromatographic Properties
Collision Cross Sections (CCS)
Adduct CCS Value (Å2) Source type Source [M-H]- 195.365164 predictedDarkChem Lite v0.1.0 [M-H]- 170.64265 predictedDeepCCS 1.0 (2019) [M-H]- 195.365164 predictedDarkChem Lite v0.1.0 [M-H]- 170.64265 predictedDeepCCS 1.0 (2019) [M+H]+ 197.046664 predictedDarkChem Lite v0.1.0 [M+H]+ 173.00066 predictedDeepCCS 1.0 (2019) [M+H]+ 197.046664 predictedDarkChem Lite v0.1.0 [M+H]+ 173.00066 predictedDeepCCS 1.0 (2019) [M+Na]+ 194.908964 predictedDarkChem Lite v0.1.0 [M+Na]+ 180.05736 predictedDeepCCS 1.0 (2019) [M+Na]+ 194.908964 predictedDarkChem Lite v0.1.0 [M+Na]+ 180.05736 predictedDeepCCS 1.0 (2019)
Targets
![](https://go.drugbank.com/assets/locked/DrugTargets2-682eb846d210ae4bf33ca03febccfb57bb1c61318e699b729e5df4dfab2c5b67.png)
- 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
- 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. [Article]
- Curreli F, Ahmed S, Victor SMB, Debnath AK: Identification of Combinations of Protein Kinase C Activators and Histone Deacetylase Inhibitors That Potently Reactivate Latent HIV. Viruses. 2020 Jun 3;12(6). pii: v12060609. doi: 10.3390/v12060609. [Article]
- FDA Label [Link]
Enzymes
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- General Function
- Steroid binding
- 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
- UGT1A1
- Uniprot ID
- P22309
- Uniprot Name
- UDP-glucuronosyltransferase 1-1
- Molecular Weight
- 59590.91 Da
References
- 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. [Article]
- 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
- 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. [Article]
- 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
- 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. [Article]
- 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 at October 21, 2007 22:23 / Updated at February 21, 2021 18:51