Identification
- Summary
Deucravacitinib is a TYK2 inhibitor being investigated as a treatment for psoriasis.
- Generic Name
- Deucravacitinib
- DrugBank Accession Number
- DB16650
- Background
Deucravacitinib is a novel oral selective tyrosine kinase 2 (TYK2) inhibitor. Unlike other Janus kinase 1/2/3 inhibitors that bind to the conserved active domain of these non-receptor tyrosine kinases, deucravacitinib binds to the regulatory domain of TYK2 with high selectivity to this therapeutic target.1,2 This selectivity towards TYK2 may lead to an improved safety profile of deucravacitinib, as nonselective JAK inhibitors are associated with a range of adverse effects such as altered cholesterol and triglyceride levels, and liver and kidney dysfunction.2
Deucravacitinib is under investigation in clinical trial NCT04772079 (A Study to Evaluate the Drug Levels, Efficacy and Safety of BMS-986165 in Adolescent Participants With Moderate to Severe Plaque Psoriasis).
- Type
- Small Molecule
- Groups
- Investigational
- Structure
Structure for Deucravacitinib (DB16650)
- Weight
- Average: 425.467
Monoisotopic: 425.200316838 - Chemical Formula
- C20H22N8O3
- Synonyms
- Deucravacitinib
- External IDs
- BMS-986165
- WHO 11342
Pharmacology
- Indication
Not Available
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Not Available
- Mechanism of action
Tyrosine kinase 2 (TYK2) is a member of the Janus kinase (JAK) family of kinases, which are intracellular tyrosine kinases that activate the JAK–signal transducer and activator of transcription pathway. Unlike other members of the JAK family that promote broader immune and extra-immune pathways such as lipid metabolism, the TYK2 signalling pathway is responsible for selected immune pathways.1 TYK2 mediates signalling of inflammatory cytokines of both adaptive (e.g., interleukin (IL) 12 and IL-23) and innate (e.g., type I interferons) immune responses.3 In particular, IL-23 has been implicated in the pathogenesis of immune-mediated disorders such as psoriasis and psoriatic arthritis.1 It activates and promotes the proliferation of Th17 cells: subsequently, Th17 cells secrete inflammatory mediators, such as IL-17 and tumor necrosis factor-alpha, that stimulate epidermal cells to produce cytokines and chemokines that attract and activate innate immune system cells.1,2 Enhanced activity of Th17 cells lead to sustained inflammatory responses in the skin and joints as manifested in psoriatic arthritis.1
Deucravacitinib inhibits TYK2 via an allosteric mechanism: it binds to the enzyme's regulatory domain - also known as the pseudokinase (JH2) domain - instead of the catalytic domain. This binding activity allows high selectivity towards TYK2 over other tyrosine kinase enzymes. In in vitro cellular assays, deucravacitinib showed a 100-fold to 2000-fold selectivity for TYK2 over JAK 1/2/3 and demonstrated minimal or no activity against JAK 1/2/3. Upon binding to TYK2, deucravacitinib induces a confirmational change and locks the regulatory domain of TYK2 into an inhibitory confirmation with the catalytic domain, trapping TYK2 in an inactive state.1,2 Inhibiting TYK2 leads to the downregulation of the IL-23/TH17 pathway, IL-12 signalling, type 1 interferon pathway, and keratinocyte activation.3
Target Actions Organism ANon-receptor tyrosine-protein kinase TYK2 inhibitorHumans - Absorption
Not Available
- Volume of distribution
Not Available
- Protein binding
Not Available
- Metabolism
- Not Available
- Route of elimination
Not Available
- Half-life
Not Available
- Clearance
Not Available
- Adverse Effects
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Not Available
- 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 softwareAbaloparatide The therapeutic efficacy of Abaloparatide can be decreased when used in combination with Deucravacitinib. Acetaminophen The serum concentration of Acetaminophen can be increased when it is combined with Deucravacitinib. Carbimazole The therapeutic efficacy of Carbimazole can be decreased when used in combination with Deucravacitinib. Follitropin The therapeutic efficacy of Follitropin can be decreased when used in combination with Deucravacitinib. Levothyroxine The therapeutic efficacy of Levothyroxine can be decreased when used in combination with Deucravacitinib. Liothyronine The therapeutic efficacy of Liothyronine can be decreased when used in combination with Deucravacitinib. Liotrix The therapeutic efficacy of Liotrix can be decreased when used in combination with Deucravacitinib. Methimazole The therapeutic efficacy of Methimazole can be decreased when used in combination with Deucravacitinib. Parathyroid hormone The therapeutic efficacy of Parathyroid hormone can be decreased when used in combination with Deucravacitinib. Potassium Iodide The therapeutic efficacy of Potassium Iodide can be decreased when used in combination with Deucravacitinib. 
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- Not Available
Products
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Ingredient UNII CAS InChI Key Deucravacitinib hydrochloride 95C5558CF4 1609392-28-0 LILQGPVDQZORJG-NIIDSAIPSA-N
Categories
- Drug Categories
- Classification
- Not classified
- Affected organisms
- Not Available
Chemical Identifiers
- UNII
- N0A21N6RAU
- CAS number
- 1609392-27-9
- InChI Key
- BZZKEPGENYLQSC-FIBGUPNXSA-N
- InChI
- InChI=1S/C20H22N8O3/c1-21-20(30)16-14(9-15(25-26-16)24-19(29)11-7-8-11)23-13-6-4-5-12(17(13)31-3)18-22-10-28(2)27-18/h4-6,9-11H,7-8H2,1-3H3,(H,21,30)(H2,23,24,25,29)/i1D3
- IUPAC Name
- 6-cyclopropaneamido-4-{[2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl]amino}-N-(2H3)methylpyridazine-3-carboxamide
- SMILES
- [2H]C([2H])([2H])NC(=O)C1=C(NC2=CC=CC(C3=NN(C)C=N3)=C2OC)C=C(NC(=O)C2CC2)N=N1
References
- General References
- Mease PJ, Deodhar AA, van der Heijde D, Behrens F, Kivitz AJ, Neal J, Kim J, Singhal S, Nowak M, Banerjee S: Efficacy and safety of selective TYK2 inhibitor, deucravacitinib, in a phase II trial in psoriatic arthritis. Ann Rheum Dis. 2022 Mar 3. pii: annrheumdis-2021-221664. doi: 10.1136/annrheumdis-2021-221664. [Article]
- Chimalakonda A, Burke J, Cheng L, Catlett I, Tagen M, Zhao Q, Patel A, Shen J, Girgis IG, Banerjee S, Throup J: Selectivity Profile of the Tyrosine Kinase 2 Inhibitor Deucravacitinib Compared with Janus Kinase 1/2/3 Inhibitors. Dermatol Ther (Heidelb). 2021 Oct;11(5):1763-1776. doi: 10.1007/s13555-021-00596-8. Epub 2021 Aug 30. [Article]
- Catlett IM, Hu Y, Gao L, Banerjee S, Gordon K, Krueger JG: Molecular and clinical effects of selective tyrosine kinase 2 inhibition with deucravacitinib in psoriasis. J Allergy Clin Immunol. 2021 Nov 10. pii: S0091-6749(21)01690-0. doi: 10.1016/j.jaci.2021.11.001. [Article]
- External Links
- ChemSpider
- 72380005
- BindingDB
- 50507816
- ChEMBL
- CHEMBL4435170
Clinical Trials
- Clinical Trials
Phase Status Purpose Conditions Count 3 Active Not Recruiting Treatment Psoriasis (PsO) 1 3 Completed Treatment Psoriasis (PsO) 4 3 Not Yet Recruiting Treatment Psoriasis (PsO) 1 3 Recruiting Treatment Psoriasis Vulgaris (Plaque Psoriasis) 1 3 Recruiting Treatment Psoriatic Arthritis 2 2 Active Not Recruiting Treatment Systemic Lupus Erythematosus (SLE) 1 2 Active Not Recruiting Treatment Ulcerative Colitis 1 2 Completed Treatment Active Psoriatic arthritis 1 2 Completed Treatment Psoriasis (PsO) 1 2 Completed Treatment Systemic Lupus Erythematosus (SLE) 1
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
- Not Available
- Prices
- Not Available
- Patents
- Not Available
Properties
- State
- Not Available
- Experimental Properties
- Not Available
- Predicted Properties
Property Value Source Water Solubility 0.159 mg/mL ALOGPS logP 1.8 ALOGPS logP 2.1 ChemAxon logS -3.4 ALOGPS pKa (Strongest Acidic) 11.09 ChemAxon pKa (Strongest Basic) 2.38 ChemAxon Physiological Charge 0 ChemAxon Hydrogen Acceptor Count 8 ChemAxon Hydrogen Donor Count 3 ChemAxon Polar Surface Area 135.95 Å2 ChemAxon Rotatable Bond Count 7 ChemAxon Refractivity 138.38 m3·mol-1 ChemAxon Polarizability 44.49 Å3 ChemAxon Number of Rings 4 ChemAxon Bioavailability 1 ChemAxon Rule of Five Yes ChemAxon Ghose Filter No ChemAxon Veber's Rule No ChemAxon MDDR-like Rule Yes ChemAxon - Predicted ADMET Features
- Not Available
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
- Not Available
Targets
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Inhibitor
- General Function
- Protein tyrosine kinase activity
- Specific Function
- Probably involved in intracellular signal transduction by being involved in the initiation of type I IFN signaling. Phosphorylates the interferon-alpha/beta receptor alpha chain.
- Gene Name
- TYK2
- Uniprot ID
- P29597
- Uniprot Name
- Non-receptor tyrosine-protein kinase TYK2
- Molecular Weight
- 133648.77 Da
References
- Mease PJ, Deodhar AA, van der Heijde D, Behrens F, Kivitz AJ, Neal J, Kim J, Singhal S, Nowak M, Banerjee S: Efficacy and safety of selective TYK2 inhibitor, deucravacitinib, in a phase II trial in psoriatic arthritis. Ann Rheum Dis. 2022 Mar 3. pii: annrheumdis-2021-221664. doi: 10.1136/annrheumdis-2021-221664. [Article]
- Chimalakonda A, Burke J, Cheng L, Catlett I, Tagen M, Zhao Q, Patel A, Shen J, Girgis IG, Banerjee S, Throup J: Selectivity Profile of the Tyrosine Kinase 2 Inhibitor Deucravacitinib Compared with Janus Kinase 1/2/3 Inhibitors. Dermatol Ther (Heidelb). 2021 Oct;11(5):1763-1776. doi: 10.1007/s13555-021-00596-8. Epub 2021 Aug 30. [Article]
- Catlett IM, Hu Y, Gao L, Banerjee S, Gordon K, Krueger JG: Molecular and clinical effects of selective tyrosine kinase 2 inhibition with deucravacitinib in psoriasis. J Allergy Clin Immunol. 2021 Nov 10. pii: S0091-6749(21)01690-0. doi: 10.1016/j.jaci.2021.11.001. [Article]
Drug created at March 24, 2021 22:54 / Updated at April 28, 2022 23:24