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Identification
- Summary
Givinostat is a histone deacetylase inhibitor indicated for the treatment of Duchenne Muscular Dystrophy (DMD).
- Brand Names
- Duvyzat
- Generic Name
- Givinostat
- DrugBank Accession Number
- DB12645
- Background
Givinostat is a small molecule histone deacetylase (HDAC) inhibitor. It has been investigated as a treatment for a variety of inflammatory diseases, like Crohn's disease and juvenile idiopathic arthritis, cancers like leukemia and lymphoma, as well as several muscular dystrophies. In the context of muscular dystrophy, inhibitors of HDAC appear to exert their therapeutic effects by targeting pathogenic processes that cause inflammation and muscle loss.4,1
Givinostat was granted FDA approval in March 2024 for the treatment of patients ≥6 years of age with Duchenne muscular dystrophy (DMD).3,4 It is the first non-steroidal drug approved to treat patients with all genetic variants of DMD.4
- Type
- Small Molecule
- Groups
- Approved, Investigational
- Structure
Structure for Givinostat (DB12645)
- Weight
- Average: 421.497
Monoisotopic: 421.200156361 - Chemical Formula
- C24H27N3O4
- Synonyms
- Givinostat
- External IDs
- ITF-2357
- ITF2357
Pharmacology
- Indication
Givinostat is indicated for the treatment of Duchenne muscular dystrophy (DMD) in patients ≥6 years of age.3
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 Duchenne muscular dystrophy (dmd) •••••••••••• •••••••••• - Contraindications & Blackbox Warnings
Prevent Adverse Drug Events TodayTap into our Clinical API for life-saving information on contraindications & blackbox warnings, population restrictions, harmful risks, & more.Avoid life-threatening adverse drug events with our Clinical API- Pharmacodynamics
The efficacy givinostat was demonstrated in a randomized, double-blind, placebo-controlled trial wherein muscle function was evaluated by measuring the change from baseline to 18 months in the time taken to ascend four stairs. Patients treated with givinostat showed statistically significant less decline in the time it took to climb four stairs compared to placebo - the mean change was 1.25 seconds for patients receiving givinostat compared to 3.03 seconds for patients receiving placebo.3,4
Givinostat causes QTc interval prolongation and should be used with caution in patients with underlying cardiac disease or in patients who are taking concomitant medications that may prolong the QT interval.3
- Mechanism of action
Givinostat is a histone deacetylase inhibitor. The precise mechanism by which givinostat exerts its therapeutic effects in patients with DMD is unknown.3
Histone deacetylases (HDACs), as the name implies, regulate the deacetylation of various proteins. The acetylation and deacetylation of histone proteins causes an increase or decrease in gene expression, respectively, with the latter function governed by HDACs. The balance between levels of histone acetylation and deacetylation plays a key role in the modulation of gene transcription and governs numerous developmental processes, being involved in the regulation of various genes associated with signal transduction, cell growth, and cell death, as well as diseases like cancers.1 HDACs can deacetylate non-histone proteins, such as p53, thereby also regulating their activity.1
Several HDAC isoforms have been implicated in skeletal muscle remodeling - under both physiological and pathological conditions - which serve to regulate fiber type specification, muscle fiber size and innervation, metabolic fuel switching, muscle development, insulin sensitivity, and exercise capacity.1 This gave rise to interest in HDACs as a potential target in the treatment of muscular dystrophies, including Duchenne Muscular Dystrophy (DMD). Consistently, HDAC expression and activity have been found altered in muscular dystrophies, suggesting a role for these enzymes in the progression of the disease.1 The inhibition of these enzymes by HDAC inhibitors such as givinostat contributes to the preservation of muscle force and morphology.1
Target Actions Organism AHistone deacetylase inhibitorHumans ATyrosine-protein kinase JAK2 inhibitorHumans AHistone deacetylase 1 inhibitorHumans - Absorption
The absolute bioavailability of givinostat has not been determined. The Tmax of givinostat occurs approximately 2-3 hours following oral administration, and steady-state is achieved within 5 to 7 days with twice daily dosing.3 Systemic exposure is proportional to the administered dose across the therapeutic dose range.
Administration with a high-fat meal resulted in a 40% increase in AUC, a 23% increase in Cmax, and a delay in Tmax of 2-3 hours.3
- Volume of distribution
According to population pharmacokinetic modeling, the estimated apparent volume of distribution of the central compartment is 160 L.2 The estimated apparent volume of distribution of the peripheral compartment is 483 L.2
- Protein binding
Givinostat is highly (~96%) protein bound in plasma.3
- Metabolism
Givinostat is extensively metabolized to several metabolites, four of which have been characterized: ITF2374, ITF2375, ITF2440, and ITF2563.3 These metabolites do not contribute to the efficacy of givinostat.3 The enzymes responsible for the metabolism of givinostat are unclear; its metabolism is not mediated by CYP450 or UGT enzymes.3
- Route of elimination
Urinary excretion of givinostat is minimal (<3%).3 The elimination of givinostat is likely driven by metabolism followed by renal and biliary excretion of the resulting metabolites.3
- Half-life
The apparent plasma elimination half-life of givinostat is approximately 6 hours.3
- Clearance
According to population pharmacokinetic modeling, the estimated apparent oral clearance of givinostat is 121 L/h.2 The estimated compartmental clearance of givinostat is 33.8 L/h.2
- 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
There are no data available regarding overdosage with givinostat. In healthy subjects administered a dose of 265.8 mg (approximately 5-fold the 53.2 mg dose recommended for DMD patients weighing 60 kg or more), an increase in QTc interval 5 hours post-administration was observed, the largest mean increase being 13.6 ms.3
- 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.
Drug Interaction Integrate drug-drug
interactions in your softwareAbemaciclib The serum concentration of Abemaciclib can be increased when it is combined with Givinostat. Acalabrutinib The serum concentration of Acalabrutinib can be increased when it is combined with Givinostat. Acebutolol The risk or severity of QTc prolongation can be increased when Acebutolol is combined with Givinostat. Acenocoumarol The serum concentration of Acenocoumarol can be increased when it is combined with Givinostat. Acrivastine The risk or severity of QTc prolongation can be increased when Acrivastine is combined with Givinostat. - Food Interactions
- Take with food. Prescribing information for givinostat recommends it be administered with food twice daily.
Products
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Ingredient UNII CAS InChI Key Givinostat hydrochloride monohydrate Not Available Not Available Not applicable - Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Duvyzat Suspension 8.86 mg/1mL Oral Italfarmaco SpA 2024-03-21 Not applicable US 
Categories
- ATC Codes
- M09AX14 — Givinostat
- Drug Categories
- Acids, Acyclic
- Amines
- Antineoplastic Agents
- Cytochrome P-450 CYP1A2 Inducers
- Cytochrome P-450 CYP1A2 Inducers (strength unknown)
- Cytochrome P-450 CYP2B6 Inducers
- Cytochrome P-450 CYP2B6 Inducers (strength unknown)
- Cytochrome P-450 CYP3A Inducers
- Cytochrome P-450 CYP3A Inhibitors
- Cytochrome P-450 CYP3A4 Inducers
- Cytochrome P-450 CYP3A4 Inducers (strength unknown)
- Cytochrome P-450 CYP3A4 Inhibitors
- Cytochrome P-450 CYP3A4 Inhibitors (strength unknown)
- Cytochrome P-450 Enzyme Inducers
- Cytochrome P-450 Enzyme Inhibitors
- Enzyme Inhibitors
- Histone Deacetylase Inhibitors
- Hydroxy Acids
- Hydroxylamines
- Musculo-Skeletal System
- OCT2 Inhibitors
- Potential QTc-Prolonging Agents
- QTc Prolonging Agents
- Chemical TaxonomyProvided by Classyfire
- Description
- This compound belongs to the class of organic compounds known as phenylcarbamic acid esters. These are ester derivatives of phenylcarbamic acids.
- Kingdom
- Organic compounds
- Super Class
- Benzenoids
- Class
- Benzene and substituted derivatives
- Sub Class
- Phenylcarbamic acid esters
- Direct Parent
- Phenylcarbamic acid esters
- Alternative Parents
- Naphthalenes / Benzoic acids and derivatives / Benzoyl derivatives / Aralkylamines / Carbamate esters / Trialkylamines / Organic carbonic acids and derivatives / Hydroxamic acids / Organopnictogen compounds / Organic oxides show 2 more
- Substituents
- Amine / Amino acid or derivatives / Aralkylamine / Aromatic homopolycyclic compound / Benzoic acid or derivatives / Benzoyl / Carbamic acid ester / Carbonic acid derivative / Carbonyl group / Carboxylic acid derivative show 12 more
- Molecular Framework
- Aromatic homopolycyclic compounds
- External Descriptors
- Not Available
- Affected organisms
- Humans
Chemical Identifiers
- UNII
- 5P60F84FBH
- CAS number
- 497833-27-9
- InChI Key
- YALNUENQHAQXEA-UHFFFAOYSA-N
- InChI
- InChI=1S/C24H27N3O4/c1-3-27(4-2)15-17-5-7-21-14-18(6-8-20(21)13-17)16-31-24(29)25-22-11-9-19(10-12-22)23(28)26-30/h5-14,30H,3-4,15-16H2,1-2H3,(H,25,29)(H,26,28)
- IUPAC Name
- {6-[(diethylamino)methyl]naphthalen-2-yl}methyl N-[4-(hydroxycarbamoyl)phenyl]carbamate
- SMILES
- CCN(CC)CC1=CC=C2C=C(COC(=O)NC3=CC=C(C=C3)C(=O)NO)C=CC2=C1
References
- General References
- Sandona M, Cavioli G, Renzini A, Cedola A, Gigli G, Coletti D, McKinsey TA, Moresi V, Saccone V: Histone Deacetylases: Molecular Mechanisms and Therapeutic Implications for Muscular Dystrophies. Int J Mol Sci. 2023 Feb 21;24(5):4306. doi: 10.3390/ijms24054306. [Article]
- Fiorentini F, Germani M, Del Bene F, Pellizzoni C, Cazzaniga S, Rocchetti M, Bettica P: Population pharmacokinetic-pharmacodynamic analysis of givinostat. Expert Opin Drug Metab Toxicol. 2023 Apr;19(4):229-238. doi: 10.1080/17425255.2023.2219839. Epub 2023 Jun 12. [Article]
- FDA Approved Drug Products: Duvyzat (givinostat) suspension for oral administration [Link]
- FDA Press Announcement: FDA Approves Nonsteroidal Treatment for Duchenne Muscular Dystrophy [Link]
- External Links
- Human Metabolome Database
- HMDB0252732
- PubChem Compound
- 9804992
- PubChem Substance
- 347828853
- ChemSpider
- 7980752
- BindingDB
- 50105329
- 2678889
- ChEBI
- 94187
- ChEMBL
- CHEMBL1213492
- ZINC
- ZINC000003820616
- PDBe Ligand
- QCM
- Wikipedia
- Givinostat
- PDB Entries
- 6uoc
Clinical Trials
- Clinical Trials
Clinical Trial & Rare Diseases Add-on Data Package
Explore 4,000+ rare diseases, orphan drugs & condition pairs, clinical trial why stopped data, & more. Preview package Phase Status Purpose Conditions Count Start Date Why Stopped 100+ additional columns Unlock 175K+ rows when you subscribe.View sample dataNot Available Terminated Treatment Juvenile Idiopathic Arthritis (JIA) 1 somestatus stop reason just information to hide 3 Completed Treatment Duchenne Muscular Dystrophy (DMD) 1 somestatus stop reason just information to hide 3 Recruiting Treatment Duchenne Muscular Dystrophy (DMD) 1 somestatus stop reason just information to hide 3 Recruiting Treatment Polycythemia Vera (PV) 1 somestatus stop reason just information to hide 2 Active Not Recruiting Treatment Chronic Myeloproliferative Neoplasms 1 somestatus stop reason just information to hide
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Suspension Oral 8.86 mg/1mL - Prices
- Not Available
- Patents
Patent Number Pediatric Extension Approved Expires (estimated) Region US9421184 No 2012-02-03 2032-02-03 US US9867799 No 2012-02-03 2032-02-03 US US10688047 No 2016-10-28 2036-10-28 US US7329689 No 2005-01-15 2025-01-15 US
Properties
- State
- Solid
- Experimental Properties
- Not Available
- Predicted Properties
Property Value Source Water Solubility 0.0052 mg/mL ALOGPS logP 4.18 ALOGPS logP 3.51 Chemaxon logS -4.9 ALOGPS pKa (Strongest Acidic) 9.99 Chemaxon pKa (Strongest Basic) 9.35 Chemaxon Physiological Charge 1 Chemaxon Hydrogen Acceptor Count 5 Chemaxon Hydrogen Donor Count 3 Chemaxon Polar Surface Area 90.9 Å2 Chemaxon Rotatable Bond Count 9 Chemaxon Refractivity 122.49 m3·mol-1 Chemaxon Polarizability 47.59 Å3 Chemaxon Number of Rings 3 Chemaxon Bioavailability 1 Chemaxon Rule of Five Yes Chemaxon Ghose Filter Yes Chemaxon Veber's Rule No Chemaxon MDDR-like Rule Yes Chemaxon - Predicted ADMET Features
- Not Available
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
Spectrum Spectrum Type Splash Key Predicted MS/MS Spectrum - 10V, Positive (Annotated) Predicted LC-MS/MS splash10-00bi-3598500000-bf58ce314e74324de79e Predicted MS/MS Spectrum - 10V, Negative (Annotated) Predicted LC-MS/MS splash10-0uds-2900100000-503630a28f39f2cc87c2 Predicted MS/MS Spectrum - 20V, Negative (Annotated) Predicted LC-MS/MS splash10-000f-5900000000-ffd05267507bdcaa3377 Predicted MS/MS Spectrum - 20V, Positive (Annotated) Predicted LC-MS/MS splash10-00kr-1439100000-919c118261cc4c1cadf0 Predicted MS/MS Spectrum - 40V, Positive (Annotated) Predicted LC-MS/MS splash10-0pb9-1901000000-def3c6e6b87bebfc6cad Predicted MS/MS Spectrum - 40V, Negative (Annotated) Predicted LC-MS/MS splash10-0006-5921000000-ccc9be85c65b98d72033 Predicted 1H NMR Spectrum 1D NMR Not Applicable Predicted 13C NMR Spectrum 1D NMR Not Applicable - Chromatographic Properties
Collision Cross Sections (CCS)
Adduct CCS Value (Å2) Source type Source [M-H]- 225.6468489 predictedDarkChem Lite v0.1.0 [M-H]- 203.70831 predictedDeepCCS 1.0 (2019) [M+H]+ 226.2010489 predictedDarkChem Lite v0.1.0 [M+H]+ 206.06631 predictedDeepCCS 1.0 (2019) [M+Na]+ 225.6820489 predictedDarkChem Lite v0.1.0 [M+Na]+ 213.90892 predictedDeepCCS 1.0 (2019)
Targets
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Use our structured and evidence-based datasets to unlock newinsights and accelerate drug research.
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- Kind
- Protein group
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Inhibitor
- General Function
- Histone deacetylase that catalyzes the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4) (PubMed:16762839, PubMed:17704056, PubMed:28497810). Histone deacetylation gives a tag for epigenetic repression and plays an important role in transcriptional regulation, cell cycle progression and developmental events (PubMed:16762839, PubMed:17704056). Histone deacetylases act via the formation of large multiprotein complexes (PubMed:16762839, PubMed:17704056). Acts as a component of the histone deacetylase NuRD complex which participates in the remodeling of chromatin (PubMed:16428440, PubMed:28977666). As part of the SIN3B complex is recruited downstream of the constitutively active genes transcriptional start sites through interaction with histones and mitigates histone acetylation and RNA polymerase II progression within transcribed regions contributing to the regulation of transcription (PubMed:21041482). Also functions as a deacetylase for non-histone targets, such as NR1D2, RELA, SP1, SP3, STAT3 and TSHZ3 (PubMed:12837748, PubMed:16285960, PubMed:16478997, PubMed:17996965, PubMed:19343227). Deacetylates SP proteins, SP1 and SP3, and regulates their function (PubMed:12837748, PubMed:16478997). Component of the BRG1-RB1-HDAC1 complex, which negatively regulates the CREST-mediated transcription in resting neurons (PubMed:19081374). Upon calcium stimulation, HDAC1 is released from the complex and CREBBP is recruited, which facilitates transcriptional activation (PubMed:19081374). Deacetylates TSHZ3 and regulates its transcriptional repressor activity (PubMed:19343227). Deacetylates 'Lys-310' in RELA and thereby inhibits the transcriptional activity of NF-kappa-B (PubMed:17000776). Deacetylates NR1D2 and abrogates the effect of KAT5-mediated relieving of NR1D2 transcription repression activity (PubMed:17996965). Component of a RCOR/GFI/KDM1A/HDAC complex that suppresses, via histone deacetylase (HDAC) recruitment, a number of genes implicated in multilineage blood cell development (By similarity). Involved in CIART-mediated transcriptional repression of the circadian transcriptional activator: CLOCK-BMAL1 heterodimer (By similarity). Required for the transcriptional repression of circadian target genes, such as PER1, mediated by the large PER complex or CRY1 through histone deacetylation (By similarity). In addition to protein deacetylase activity, also has protein-lysine deacylase activity: acts as a protein decrotonylase by mediating decrotonylation ((2E)-butenoyl) of histones (PubMed:28497810)
- Specific Function
- core promoter sequence-specific DNA binding
Components:
References
- Arya Y, Syal A, Gupta M, Gaba S: Advances in the Treatment of Polycythemia Vera: Trends in Disease Management. Cureus. 2021 Mar 30;13(3):e14193. doi: 10.7759/cureus.14193. [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]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Inhibitor
- General Function
- Non-receptor tyrosine kinase involved in various processes such as cell growth, development, differentiation or histone modifications. Mediates essential signaling events in both innate and adaptive immunity. In the cytoplasm, plays a pivotal role in signal transduction via its association with type I receptors such as growth hormone (GHR), prolactin (PRLR), leptin (LEPR), erythropoietin (EPOR), thrombopoietin (THPO); or type II receptors including IFN-alpha, IFN-beta, IFN-gamma and multiple interleukins (PubMed:7615558, PubMed:9657743, PubMed:15690087). Following ligand-binding to cell surface receptors, phosphorylates specific tyrosine residues on the cytoplasmic tails of the receptor, creating docking sites for STATs proteins (PubMed:9618263, PubMed:15690087). Subsequently, phosphorylates the STATs proteins once they are recruited to the receptor. Phosphorylated STATs then form homodimer or heterodimers and translocate to the nucleus to activate gene transcription. For example, cell stimulation with erythropoietin (EPO) during erythropoiesis leads to JAK2 autophosphorylation, activation, and its association with erythropoietin receptor (EPOR) that becomes phosphorylated in its cytoplasmic domain (PubMed:9657743). Then, STAT5 (STAT5A or STAT5B) is recruited, phosphorylated and activated by JAK2. Once activated, dimerized STAT5 translocates into the nucleus and promotes the transcription of several essential genes involved in the modulation of erythropoiesis. Part of a signaling cascade that is activated by increased cellular retinol and that leads to the activation of STAT5 (STAT5A or STAT5B) (PubMed:21368206). In addition, JAK2 mediates angiotensin-2-induced ARHGEF1 phosphorylation (PubMed:20098430). Plays a role in cell cycle by phosphorylating CDKN1B (PubMed:21423214). Cooperates with TEC through reciprocal phosphorylation to mediate cytokine-driven activation of FOS transcription. In the nucleus, plays a key role in chromatin by specifically mediating phosphorylation of 'Tyr-41' of histone H3 (H3Y41ph), a specific tag that promotes exclusion of CBX5 (HP1 alpha) from chromatin (PubMed:19783980)
- Specific Function
- acetylcholine receptor binding
- Gene Name
- JAK2
- Uniprot ID
- O60674
- Uniprot Name
- Tyrosine-protein kinase JAK2
- Molecular Weight
- 130672.475 Da
References
- Zhou Y, Zhang Y, Zhao D, Yu X, Shen X, Zhou Y, Wang S, Qiu Y, Chen Y, Zhu F: TTD: Therapeutic Target Database describing target druggability information. Nucleic Acids Res. 2024 Jan 5;52(D1):D1465-D1477. doi: 10.1093/nar/gkad751. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Inhibitor
- General Function
- Histone deacetylase that catalyzes the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4) (PubMed:16762839, PubMed:17704056, PubMed:28497810). Histone deacetylation gives a tag for epigenetic repression and plays an important role in transcriptional regulation, cell cycle progression and developmental events (PubMed:16762839, PubMed:17704056). Histone deacetylases act via the formation of large multiprotein complexes (PubMed:16762839, PubMed:17704056). Acts as a component of the histone deacetylase NuRD complex which participates in the remodeling of chromatin (PubMed:16428440, PubMed:28977666). As part of the SIN3B complex is recruited downstream of the constitutively active genes transcriptional start sites through interaction with histones and mitigates histone acetylation and RNA polymerase II progression within transcribed regions contributing to the regulation of transcription (PubMed:21041482). Also functions as a deacetylase for non-histone targets, such as NR1D2, RELA, SP1, SP3, STAT3 and TSHZ3 (PubMed:12837748, PubMed:16285960, PubMed:16478997, PubMed:17996965, PubMed:19343227). Deacetylates SP proteins, SP1 and SP3, and regulates their function (PubMed:12837748, PubMed:16478997). Component of the BRG1-RB1-HDAC1 complex, which negatively regulates the CREST-mediated transcription in resting neurons (PubMed:19081374). Upon calcium stimulation, HDAC1 is released from the complex and CREBBP is recruited, which facilitates transcriptional activation (PubMed:19081374). Deacetylates TSHZ3 and regulates its transcriptional repressor activity (PubMed:19343227). Deacetylates 'Lys-310' in RELA and thereby inhibits the transcriptional activity of NF-kappa-B (PubMed:17000776). Deacetylates NR1D2 and abrogates the effect of KAT5-mediated relieving of NR1D2 transcription repression activity (PubMed:17996965). Component of a RCOR/GFI/KDM1A/HDAC complex that suppresses, via histone deacetylase (HDAC) recruitment, a number of genes implicated in multilineage blood cell development (By similarity). Involved in CIART-mediated transcriptional repression of the circadian transcriptional activator: CLOCK-BMAL1 heterodimer (By similarity). Required for the transcriptional repression of circadian target genes, such as PER1, mediated by the large PER complex or CRY1 through histone deacetylation (By similarity). In addition to protein deacetylase activity, also has protein-lysine deacylase activity: acts as a protein decrotonylase by mediating decrotonylation ((2E)-butenoyl) of histones (PubMed:28497810)
- Specific Function
- core promoter sequence-specific DNA binding
- Gene Name
- HDAC1
- Uniprot ID
- Q13547
- Uniprot Name
- Histone deacetylase 1
- Molecular Weight
- 55102.615 Da
References
- Zhou Y, Zhang Y, Zhao D, Yu X, Shen X, Zhou Y, Wang S, Qiu Y, Chen Y, Zhu F: TTD: Therapeutic Target Database describing target druggability information. Nucleic Acids Res. 2024 Jan 5;52(D1):D1465-D1477. doi: 10.1093/nar/gkad751. [Article]
Enzymes
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- InhibitorInducer
- General Function
- A cytochrome P450 monooxygenase involved in the metabolism of sterols, steroid hormones, retinoids and fatty acids (PubMed:10681376, PubMed:11093772, PubMed:11555828, PubMed:12865317, PubMed:14559847, PubMed:15373842, PubMed:15764715, PubMed:19965576, PubMed:20702771, PubMed:21490593, PubMed:21576599). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase). Catalyzes the hydroxylation of carbon-hydrogen bonds (PubMed:12865317, PubMed:14559847, PubMed:15373842, PubMed:15764715, PubMed:21490593, PubMed:21576599, PubMed:2732228). Exhibits high catalytic activity for the formation of hydroxyestrogens from estrone (E1) and 17beta-estradiol (E2), namely 2-hydroxy E1 and E2, as well as D-ring hydroxylated E1 and E2 at the C-16 position (PubMed:11555828, PubMed:12865317, PubMed:14559847). Plays a role in the metabolism of androgens, particularly in oxidative deactivation of testosterone (PubMed:15373842, PubMed:15764715, PubMed:22773874, PubMed:2732228). Metabolizes testosterone to less biologically active 2beta- and 6beta-hydroxytestosterones (PubMed:15373842, PubMed:15764715, PubMed:2732228). Contributes to the formation of hydroxycholesterols (oxysterols), particularly A-ring hydroxylated cholesterol at the C-4beta position, and side chain hydroxylated cholesterol at the C-25 position, likely contributing to cholesterol degradation and bile acid biosynthesis (PubMed:21576599). Catalyzes bisallylic hydroxylation of polyunsaturated fatty acids (PUFA) (PubMed:9435160). Catalyzes the epoxidation of double bonds of PUFA with a preference for the last double bond (PubMed:19965576). Metabolizes endocannabinoid arachidonoylethanolamide (anandamide) to 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acid ethanolamides (EpETrE-EAs), potentially modulating endocannabinoid system signaling (PubMed:20702771). Plays a role in the metabolism of retinoids. Displays high catalytic activity for oxidation of all-trans-retinol to all-trans-retinal, a rate-limiting step for the biosynthesis of all-trans-retinoic acid (atRA) (PubMed:10681376). Further metabolizes atRA toward 4-hydroxyretinoate and may play a role in hepatic atRA clearance (PubMed:11093772). Responsible for oxidative metabolism of xenobiotics. Acts as a 2-exo-monooxygenase for plant lipid 1,8-cineole (eucalyptol) (PubMed:11159812). Metabolizes the majority of the administered drugs. Catalyzes sulfoxidation of the anthelmintics albendazole and fenbendazole (PubMed:10759686). Hydroxylates antimalarial drug quinine (PubMed:8968357). Acts as a 1,4-cineole 2-exo-monooxygenase (PubMed:11695850). Also involved in vitamin D catabolism and calcium homeostasis. Catalyzes the inactivation of the active hormone calcitriol (1-alpha,25-dihydroxyvitamin D(3)) (PubMed:29461981)
- Specific Function
- 1,8-cineole 2-exo-monooxygenase activity
- Gene Name
- CYP3A4
- Uniprot ID
- P08684
- Uniprot Name
- Cytochrome P450 3A4
- Molecular Weight
- 57342.67 Da
References
- FDA Approved Drug Products: Duvyzat (givinostat) suspension for oral administration [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Inducer
- General Function
- A cytochrome P450 monooxygenase involved in the metabolism of various endogenous substrates, including fatty acids, steroid hormones and vitamins (PubMed:10681376, PubMed:11555828, PubMed:12865317, PubMed:19965576, PubMed:9435160). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase) (PubMed:10681376, PubMed:11555828, PubMed:12865317, PubMed:19965576, PubMed:9435160). Catalyzes the hydroxylation of carbon-hydrogen bonds (PubMed:11555828, PubMed:12865317). Exhibits high catalytic activity for the formation of hydroxyestrogens from estrone (E1) and 17beta-estradiol (E2), namely 2-hydroxy E1 and E2 (PubMed:11555828, PubMed:12865317). Metabolizes cholesterol toward 25-hydroxycholesterol, a physiological regulator of cellular cholesterol homeostasis (PubMed:21576599). May act as a major enzyme for all-trans retinoic acid biosynthesis in the liver. Catalyzes two successive oxidative transformation of all-trans retinol to all-trans retinal and then to the active form all-trans retinoic acid (PubMed:10681376). Primarily catalyzes stereoselective epoxidation of the last double bond of polyunsaturated fatty acids (PUFA), displaying a strong preference for the (R,S) stereoisomer (PubMed:19965576). Catalyzes bisallylic hydroxylation and omega-1 hydroxylation of PUFA (PubMed:9435160). May also participate in eicosanoids metabolism by converting hydroperoxide species into oxo metabolites (lipoxygenase-like reaction, NADPH-independent) (PubMed:21068195). Plays a role in the oxidative metabolism of xenobiotics. Catalyzes the N-hydroxylation of heterocyclic amines and the O-deethylation of phenacetin (PubMed:14725854). Metabolizes caffeine via N3-demethylation (Probable)
- Specific Function
- aromatase activity
- Gene Name
- CYP1A2
- Uniprot ID
- P05177
- Uniprot Name
- Cytochrome P450 1A2
- Molecular Weight
- 58406.915 Da
References
- FDA Approved Drug Products: Duvyzat (givinostat) suspension for oral administration [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Inducer
- General Function
- A cytochrome P450 monooxygenase involved in the metabolism of endocannabinoids and steroids (PubMed:12865317, PubMed:21289075). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase). Catalyzes the epoxidation of double bonds of arachidonoylethanolamide (anandamide) to 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acid ethanolamides (EpETrE-EAs), potentially modulating endocannabinoid system signaling (PubMed:21289075). Hydroxylates steroid hormones, including testosterone at C-16 and estrogens at C-2 (PubMed:12865317, PubMed:21289075). Plays a role in the oxidative metabolism of xenobiotics, including plant lipids and drugs (PubMed:11695850, PubMed:22909231). Acts as a 1,4-cineole 2-exo-monooxygenase (PubMed:11695850)
- Specific Function
- anandamide 11,12 epoxidase activity
- Gene Name
- CYP2B6
- Uniprot ID
- P20813
- Uniprot Name
- Cytochrome P450 2B6
- Molecular Weight
- 56277.81 Da
References
- FDA Approved Drug Products: Duvyzat (givinostat) suspension for oral administration [Link]
Transporters
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Inhibitor
- General Function
- Electrogenic voltage-dependent transporter that mediates the transport of a variety of organic cations such as endogenous bioactive amines, cationic drugs and xenobiotics (PubMed:9260930, PubMed:9687576). Functions as a Na(+)-independent, bidirectional uniporter (PubMed:21128598, PubMed:9687576). Cation cellular uptake or release is driven by the electrochemical potential, i.e. membrane potential and concentration gradient (PubMed:15212162, PubMed:9260930, PubMed:9687576). However, may also engage electroneutral cation exchange when saturating concentrations of cation substrates are reached (By similarity). Predominantly expressed at the basolateral membrane of hepatocytes and proximal tubules and involved in the uptake and disposition of cationic compounds by hepatic and renal clearance from the blood flow (PubMed:15783073). Implicated in monoamine neurotransmitters uptake such as histamine, dopamine, adrenaline/epinephrine, noradrenaline/norepinephrine, serotonin and tyramine, thereby supporting a physiological role in the central nervous system by regulating interstitial concentrations of neurotransmitters (PubMed:16581093, PubMed:17460754, PubMed:9687576). Also capable of transporting dopaminergic neuromodulators cyclo(his-pro), salsolinol and N-methyl-salsolinol, thereby involved in the maintenance of dopaminergic cell integrity in the central nervous system (PubMed:17460754). Mediates the bidirectional transport of acetylcholine (ACh) at the apical membrane of ciliated cell in airway epithelium, thereby playing a role in luminal release of ACh from bronchial epithelium (PubMed:15817714). Also transports guanidine and endogenous monoamines such as vitamin B1/thiamine, creatinine and N-1-methylnicotinamide (NMN) (PubMed:12089365, PubMed:15212162, PubMed:17072098, PubMed:24961373, PubMed:9260930). Mediates the uptake and efflux of quaternary ammonium compound choline (PubMed:9260930). Mediates the bidirectional transport of polyamine agmatine and the uptake of polyamines putrescine and spermidine (PubMed:12538837, PubMed:21128598). Able to transport non-amine endogenous compounds such as prostaglandin E2 (PGE2) and prostaglandin F2-alpha (PGF2-alpha) (PubMed:11907186). Also involved in the uptake of xenobiotic 4-(4-(dimethylamino)styryl)-N-methylpyridinium (ASP) (PubMed:12395288, PubMed:16394027). May contribute to regulate the transport of organic compounds in testis across the blood-testis-barrier (Probable)
- Specific Function
- acetylcholine transmembrane transporter activity
- Gene Name
- SLC22A2
- Uniprot ID
- O15244
- Uniprot Name
- Solute carrier family 22 member 2
- Molecular Weight
- 62579.99 Da
References
- FDA Approved Drug Products: Duvyzat (givinostat) suspension for oral administration [Link]
Drug created at October 20, 2016 23:24 / Updated at August 26, 2024 19:23