This drug entry is a stub and has not been fully annotated. It is scheduled to be annotated soon.

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
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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Contraindications & Blackbox Warnings
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Pharmacodynamics

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

TargetActionsOrganism
ANon-receptor tyrosine-protein kinase TYK2
inhibitor
Humans
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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Toxicity

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.
DrugInteraction
AbaloparatideThe therapeutic efficacy of Abaloparatide can be decreased when used in combination with Deucravacitinib.
AcetaminophenThe serum concentration of Acetaminophen can be increased when it is combined with Deucravacitinib.
CarbimazoleThe therapeutic efficacy of Carbimazole can be decreased when used in combination with Deucravacitinib.
FollitropinThe therapeutic efficacy of Follitropin can be decreased when used in combination with Deucravacitinib.
LevothyroxineThe therapeutic efficacy of Levothyroxine can be decreased when used in combination with Deucravacitinib.
LiothyronineThe therapeutic efficacy of Liothyronine can be decreased when used in combination with Deucravacitinib.
LiotrixThe therapeutic efficacy of Liotrix can be decreased when used in combination with Deucravacitinib.
MethimazoleThe therapeutic efficacy of Methimazole can be decreased when used in combination with Deucravacitinib.
Parathyroid hormoneThe therapeutic efficacy of Parathyroid hormone can be decreased when used in combination with Deucravacitinib.
Potassium IodideThe therapeutic efficacy of Potassium Iodide can be decreased when used in combination with Deucravacitinib.
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Food Interactions
Not Available

Products

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Product Ingredients
IngredientUNIICASInChI Key
Deucravacitinib hydrochloride95C5558CF41609392-28-0LILQGPVDQZORJG-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
  1. 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]
  2. 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]
  3. 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]
ChemSpider
72380005
BindingDB
50507816
ChEMBL
CHEMBL4435170

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3Active Not RecruitingTreatmentPsoriasis (PsO)1
3CompletedTreatmentPsoriasis (PsO)4
3Not Yet RecruitingTreatmentPsoriasis (PsO)1
3RecruitingTreatmentPsoriasis Vulgaris (Plaque Psoriasis)1
3RecruitingTreatmentPsoriatic Arthritis2
2Active Not RecruitingTreatmentSystemic Lupus Erythematosus (SLE)1
2Active Not RecruitingTreatmentUlcerative Colitis1
2CompletedTreatmentActive Psoriatic arthritis1
2CompletedTreatmentPsoriasis (PsO)1
2CompletedTreatmentSystemic 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
PropertyValueSource
Water Solubility0.159 mg/mLALOGPS
logP1.8ALOGPS
logP2.1ChemAxon
logS-3.4ALOGPS
pKa (Strongest Acidic)11.09ChemAxon
pKa (Strongest Basic)2.38ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count8ChemAxon
Hydrogen Donor Count3ChemAxon
Polar Surface Area135.95 Å2ChemAxon
Rotatable Bond Count7ChemAxon
Refractivity138.38 m3·mol-1ChemAxon
Polarizability44.49 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
Not Available

Targets

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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
  1. 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]
  2. 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]
  3. 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