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tyrosine kinase 2

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Immunopharmacology Ligand target has curated data in GtoImmuPdb

Target id: 2269

Nomenclature: tyrosine kinase 2

Abbreviated Name: Tyk2

Family: Janus kinase (JakA) family

Contents:

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 1187 19p13.2 TYK2 tyrosine kinase 2
Mouse - 1184 9 A3 Tyk2 tyrosine kinase 2
Rat - 1186 8q13 Tyk2 tyrosine kinase 2
Previous and Unofficial Names Click here for help
JTK1
Database Links Click here for help
Alphafold P29597 (Hs), Q9R117 (Mm)
BRENDA 2.7.10.2
CATH/Gene3D 1.20.80.10, 3.30.505.10
ChEMBL Target CHEMBL3553 (Hs), CHEMBL2321619 (Mm)
Ensembl Gene ENSG00000105397 (Hs), ENSMUSG00000032175 (Mm), ENSRNOG00000032948 (Rn)
Entrez Gene 7297 (Hs), 54721 (Mm), 100361294 (Rn)
Human Protein Atlas ENSG00000105397 (Hs)
KEGG Enzyme 2.7.10.2
KEGG Gene hsa:7297 (Hs), mmu:54721 (Mm), rno:100361294 (Rn)
OMIM 176941 (Hs)
Orphanet ORPHA159075 (Hs)
Pharos P29597 (Hs)
RefSeq Nucleotide NM_003331 (Hs), NM_001205312 (Mm), NM_001257347 (Rn)
RefSeq Protein NP_003322 (Hs), NP_001192241 (Mm), NP_001244276 (Rn)
SynPHARM 80438 (in complex with JAK inhibitor I)
85284 (in complex with tofacitinib)
UniProtKB P29597 (Hs), Q9R117 (Mm)
Wikipedia TYK2 (Hs)
Selected 3D Structures Click here for help
Image of receptor 3D structure from RCSB PDB
Description:  Non-phosphorylated TYK2 kinase with CMP6.
PDB Id:  3NZ0
Ligand:  JAK inhibitor I
Resolution:  2.0Å
Species:  Human
References:  45
Image of receptor 3D structure from RCSB PDB
Description:  Structural and thermodynamic characterization of the TYK2 and JAK3 kinase domains in complex with CP-690550 and CMP-6.
PDB Id:  3LXP
Ligand:  tofacitinib
Resolution:  1.65Å
Species:  Human
References:  9
Image of receptor 3D structure from RCSB PDB
Description:  Tyk2 with compound 23
PDB Id:  6DBM
Ligand:  brepocitinib
Resolution:  2.368Å
Species:  Human
References:  18
Enzyme Reaction Click here for help
EC Number: 2.7.10.2

Download all structure-activity data for this target as a CSV file go icon to follow link

Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
izencitinib Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition 9.0 – 10.0 pKi 24
⤷ pKi 9.0 – 10.0 (Ki 1x10-9 – 1x10-10 M) [24]
nezulcitinib Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition 8.6 pKi 30
⤷ pKi 8.6 (Ki 2.5x10-9 M) [30]
GDC-0214 Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition 8.5 pKi 14
⤷ pKi 8.5 (Ki 3.15x10-9 M) [14]
delgocitinib Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition 7.8 pKi 42
⤷ pKi 7.8 (Ki 1.4x10-8 M) [42]
Description: In an assay using the kinase domain of the recombinant human enzyme, a biotinylated peptide substrate, and [33P]ATP.
cerdulatinib Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition 9.3 pIC50 11
⤷ pIC50 9.3 (IC50 5x10-10 M) [11]
JAK inhibitor I Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 9.0 pIC50 17
⤷ pIC50 9.0 (IC50 1x10-9 M) [17]
SAR-20347 Small molecule or natural product Primary target of this compound Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition 7.9 – 9.2 pIC50 1
⤷ pIC50 9.2 (IC50 6x10-10 M)
Description: In a 33P-ATP assay.
pIC50 7.9 (IC50 1.3x10-8 M) [1]
Description: In a TR-FRET assay.
compound 29 [Moslin et al., 2017] Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition 8.4 pIC50 33
⤷ pIC50 8.4 (IC50 4x10-9 M) [33]
Description: Measuring binding to the JH2 pseudokinase domain of human TYK2.
ruxolitinib Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition 7.5 – 9.3 pIC50 10,22
⤷ pIC50 9.3 (IC50 5.5x10-10 M) [22]
pIC50 7.5 (IC50 3x10-8 M) [10]
peficitinib Small molecule or natural product Approved drug Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition 8.3 pIC50 26
⤷ pIC50 8.3 (IC50 5x10-9 M) [26]
lorpucitinib Small molecule or natural product Click here for species-specific activity table Hs Inhibition 8.1 pIC50 28
⤷ pIC50 8.1 (IC50 7.4x10-9 M) [28]
Description: Determined in a biochemical high-throughput mass spectrometry (HTMS) assay.
TYK2 inhibitor 14l Small molecule or natural product Primary target of this compound Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition 8.1 pIC50 51
⤷ pIC50 8.1 (IC50 9x10-9 M) [51]
zotiraciclib Small molecule or natural product Click here for species-specific activity table Hs Inhibition 7.8 pIC50 20
⤷ pIC50 7.8 (IC50 1.4x10-8 M) [20]
ropsacitinib Small molecule or natural product Click here for species-specific activity table Hs Inhibition 7.8 pIC50 19
⤷ pIC50 7.8 (IC50 1.5x10-8 M) [19]
momelotinib Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 7.7 pIC50 3
⤷ pIC50 7.7 (IC50 1.99x10-8 M) [3]
ilginatinib Small molecule or natural product Click here for species-specific activity table Hs Inhibition 7.7 pIC50 35
⤷ pIC50 7.7 (IC50 2.2x10-8 M) [35]
brepocitinib Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition 7.6 pIC50 18
⤷ pIC50 7.6 (IC50 2.3x10-8 M) [18]
PF-06263276 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition 7.5 pIC50 27
⤷ pIC50 7.5 (IC50 2.97x10-8 M) [27]
JAK inhibitor 17b Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition 7.4 pIC50 16
⤷ pIC50 7.4 (IC50 3.94x10-8 M) [16]
compound 13 [PMID: 34333981] Small molecule or natural product Click here for species-specific activity table Hs Inhibition 7.3 pIC50 15
⤷ pIC50 7.3 (IC50 4.8x10-8 M) [15]
CEE321 Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition 7.3 pIC50 43
⤷ pIC50 7.3 (IC50 5x10-8 M) [43]
delgocitinib Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition 7.2 pIC50 36
⤷ pIC50 7.2 (IC50 5.8x10-8 M) [36]
baricitinib Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition 7.2 pIC50 10
⤷ pIC50 7.2 (IC50 6.1x10-8 M) [10]
BMS-911543 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 7.2 pIC50 38
⤷ pIC50 7.2 (IC50 6.6x10-8 M) [38]
compound 6 [PMID: 34333981] Small molecule or natural product Click here for species-specific activity table Hs Inhibition 7.2 pIC50 15
⤷ pIC50 7.2 (IC50 6.7x10-8 M) [15]
JAK inhibitor 20a Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition 7.1 pIC50 16
⤷ pIC50 7.1 (IC50 7.37x10-8 M) [16]
oclacitinib Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition 7.1 pIC50 5
⤷ pIC50 7.1 (IC50 7.51x10-8 M) [5]
compound 13ac [PMID: 33256400] Small molecule or natural product Click here for species-specific activity table Hs Inhibition 7.1 pIC50 50
⤷ pIC50 7.1 (IC50 7.5x10-8 M) [50]
zasocitinib Small molecule or natural product Immunopharmacology Ligand Hs Inhibition >7.0 pIC50 32
⤷ pIC50 >7.0 (IC50 <1x10-7 M) [32]
Description: Inhibition of IL-12 Induced STAT4 phosphorylation as mediated by Tyk2/JAK2 heterodimeric complex
LASW1393 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition 6.9 pIC50 4
⤷ pIC50 6.9 (IC50 1.3x10-7 M) [4]
PF-956980 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 6.9 pIC50 21
⤷ pIC50 6.9 (IC50 1.28x10-7 M) [21]
fedratinib Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 6.8 pIC50 31
⤷ pIC50 6.8 (IC50 1.5x10-7 M) [31]
solcitinib Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition 6.7 pIC50 6
⤷ pIC50 6.7 (IC50 2.19x10-7 M) [6]
tofacitinib Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition 6.3 pIC50 10
⤷ pIC50 6.3 (IC50 4.89x10-7 M) [10]
Description: In a biochemical enzyme assay.
filgotinib Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition 5.6 – 6.9 pIC50 10,46
⤷ pIC50 6.9 (IC50 1.16x10-7 M) [46]
pIC50 5.6 (IC50 2.6x10-6 M) [10]
compound 30 [PMID: 37057760] Small molecule or natural product Click here for species-specific activity table Hs Inhibition 6.1 pIC50 39
⤷ pIC50 6.1 (IC50 7.804x10-7 M) [39]
golidocitinib Small molecule or natural product Click here for species-specific activity table Hs Inhibition 5.6 pIC50 41
⤷ pIC50 5.6 (IC50 2.8x10-6 M) [41]
Description: Inhbition of TYK2 enzymatic activity.
upadacitinib Small molecule or natural product Approved drug Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition 5.3 pIC50 47
⤷ pIC50 5.3 (IC50 4.7x10-6 M) [47]
JAK3 inhibitor 32 Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition <5.0 pIC50 7
⤷ pIC50 <5.0 (IC50 >1x10-5 M) [7]
JAK3 inhibitor 34 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition <5.0 pIC50 7
⤷ pIC50 <5.0 (IC50 >1x10-5 M) [7]
Inhibitor Comments
The IC50 for decernotinib vs. TYK2 is >10 μM [10].
Allosteric Modulators
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
deucravacitinib Small molecule or natural product Approved drug Primary target of this compound Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition 10.7 pKi 49
⤷ pKi 10.7 (Ki 2x10-11 M) [49]
Description: Determined in a Morrison titration by varying the concentration of the fluorescent probe in the TYK2 JH2 assay.
deucravacitinib Small molecule or natural product Approved drug Primary target of this compound Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition 9.7 pIC50 49
⤷ pIC50 9.7 (IC50 2x10-10 M) [49]
Description: Binding to TYK2's JH2 pseudokinase domain in a biochemical binding assay.
Other Binding Ligands
Key to terms and symbols Click column headers to sort
Ligand Sp. Action Value Parameter Reference
SJ988497 Small molecule or natural product Click here for species-specific activity table Hs Binding 9.3 pKd 8
⤷ pKd 9.3 (Kd 5.4x10-10 M) [8]
DiscoveRx KINOMEscan® screen Click here for help
A screen of 72 inhibitors against 456 human kinases. Quantitative data were derived using DiscoveRx KINOMEscan® platform.
http://www.discoverx.com/services/drug-discovery-development-services/kinase-profiling/kinomescan
Reference: 13,48
Key to terms and symbols Click column headers to sort
Target used in screen: TYK2(JH1domain-catalytic)
Ligand Sp. Type Action Value Parameter
ruxolitinib Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 9.1 pKd
tofacitinib Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 8.3 pKd
JNJ-28312141 Small molecule or natural product Hs Inhibitor Inhibition 8.2 pKd
lestaurtinib Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 7.8 pKd
fedratinib Small molecule or natural product Approved drug Ligand has a PDB structure Hs Inhibitor Inhibition 7.7 pKd
staurosporine Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 7.3 pKd
NVP-TAE684 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 7.1 pKd
dovitinib Small molecule or natural product Hs Inhibitor Inhibition 6.8 pKd
KW-2449 Small molecule or natural product Hs Inhibitor Inhibition 6.8 pKd
alvocidib Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 6.7 pKd
Target used in screen: TYK2(JH2domain-pseudokinase)
Ligand Sp. Type Action Value Parameter
alvocidib Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 7.5 pKd
dasatinib Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 7.0 pKd
sunitinib Small molecule or natural product Approved drug Ligand has a PDB structure Hs Inhibitor Inhibition 6.4 pKd
fedratinib Small molecule or natural product Approved drug Ligand has a PDB structure Hs Inhibitor Inhibition 6.3 pKd
JNJ-28312141 Small molecule or natural product Hs Inhibitor Inhibition 6.3 pKd
MLN-120B Small molecule or natural product Immunopharmacology Ligand Hs Inhibitor Inhibition 6.3 pKd
KW-2449 Small molecule or natural product Hs Inhibitor Inhibition 6.3 pKd
SU-14813 Small molecule or natural product Hs Inhibitor Inhibition 6.1 pKd
TG-100-115 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 6.1 pKd
lestaurtinib Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 6.0 pKd
Displaying the top 10 most potent ligands  View all ligands in screen »
EMD Millipore KinaseProfilerTM screen/Reaction Biology Kinase HotspotSM screen Click here for help
A screen profiling 158 kinase inhibitors (Calbiochem Protein Kinase Inhibitor Library I and II, catalogue numbers 539744 and 539745) for their inhibitory activity at 1µM and 10µM against 234 human recombinant kinases using the EMD Millipore KinaseProfilerTM service.

A screen profiling the inhibitory activity of 178 commercially available kinase inhibitors at 0.5µM against a panel of 300 recombinant protein kinases using the Reaction Biology Corporation Kinase HotspotSM platform.

http://www.millipore.com/techpublications/tech1/pf3036
http://www.reactionbiology.com/webapps/main/pages/kinase.aspx

Reference: ...2
Key to terms and symbols Click column headers to sort
Target used in screen: nd/TYK2
Ligand Sp. Type Action % Activity remaining at 0.5µM % Activity remaining at 1µM % Activity remaining at 10µM
JNJ-7706621 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 0.9
K-252a Small molecule or natural product Hs Inhibitor Inhibition 0.9
JAK inhibitor I Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 1.5
staurosporine Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 1.9
Gö 6976 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 2.6
SB 218078 Small molecule or natural product Hs Inhibitor Inhibition 4.3
Cdk2 inhibitor IV Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 5.0
Cdk1/2 inhibitor III Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 5.1
IKK-2 inhibitor IV Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 6.3
midostaurin Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 8.3
Displaying the top 10 most potent ligands  View all ligands in screen »
Immunopharmacology Comments
TYK2 was the first member of the Janus kinase family to be identified. It associates with the cytoplasmic domain of type I and type II cytokine receptors, where it phosphorylates receptor subunits and facilitates signalling downstream of the receptors for the p40-containing cytokines IL-12 and IL-23 via activation of STAT-dependent transcription factors. It also mediates Type I IFN-driven responses [40]. TYK2 activity mediates cytokine-driven immune and pro-inflammatory signalling pathways that are key components in the cycle of chronic inflammation that drives the pathophysiology of immune-mediated diseases including psoriasis [25] and arthritic psoriasis, systemic lupus erythematosus and inflammatory bowel diseases.

Small molecules that inhibit TYK2 are being actively developed as novel therapeutics for the above conditions [23,34]. TYK2 selectivity has been achieved by targeting the protein's pseudokinase (Jak homology 2 or JH2) domain [29,44], rather than the functional kinase (or JH1) domain which shares a high degree of homology across all members of the Janus kinase family and offers little selectivity. Identified molecules act as negative allosteric modulators (NAM) of TYK2 activity. One particular example of a clinical candidate TYK2 NAM is deucravacitinib (BMS-986165), which is an orally active compound that has progressed to Phase 3 clinical evaluation in patients with psoriasis [37], and is the first truly TYK2 selective inhibitor. Clinical trials are in earlier stages for a spectrum of chronic autoimmune diseases. Click here to link to ClinicalTrials.gov's full list of BMS-986165 studies. Nimbus Therapeutics are also developing allosteric TYK2 inhibitors (claimed in their patent WO2016138352 [12]), although no clinical leads have been disclosed (July 2021).
Immuno Process Associations
Immuno Process:  Inflammation
GO Annotations:  Associated to 2 GO processes
GO:0038196 type III interferon-mediated signaling pathway IC
GO:0060337 type I interferon-mediated signaling pathway TAS
Immuno Process:  Cytokine production & signalling
GO Annotations:  Associated to 5 GO processes
GO:0019221 cytokine-mediated signaling pathway IBA
GO:0032729 positive regulation of type II interferon production IDA
GO:0032740 positive regulation of interleukin-17 production IC
GO:0038196 type III interferon-mediated signaling pathway IC
GO:0060337 type I interferon-mediated signaling pathway TAS
Immuno Process:  B cell (activation)
GO Annotations:  Associated to 1 GO processes
GO:2000318 positive regulation of T-helper 17 type immune response IC
Immuno Process:  Cellular signalling
GO Annotations:  Associated to 3 GO processes
GO:0032819 positive regulation of natural killer cell proliferation IDA
GO:0042102 positive regulation of T cell proliferation IDA
GO:0051142 positive regulation of NK T cell proliferation IDA
Immuno Process:  Chemotaxis & migration
GO Annotations:  Associated to 2 GO processes
GO:0042102 positive regulation of T cell proliferation IDA
GO:0051142 positive regulation of NK T cell proliferation IDA
Immuno Process:  Immune regulation
GO Annotations:  Associated to 4 GO processes
GO:0032819 positive regulation of natural killer cell proliferation IDA
GO:0042102 positive regulation of T cell proliferation IDA
GO:0051142 positive regulation of NK T cell proliferation IDA
GO:2000318 positive regulation of T-helper 17 type immune response IC
Immuno Process:  T cell (activation)
GO Annotations:  Associated to 3 GO processes
GO:0042102 positive regulation of T cell proliferation IDA
GO:0051142 positive regulation of NK T cell proliferation IDA
GO:2000318 positive regulation of T-helper 17 type immune response IC
Clinically-Relevant Mutations and Pathophysiology Click here for help
Disease:  Immunodeficiency 35; IMD35
Synonyms: Autosomal recessive hyper-IgE syndrome due to TYK2 deficiency [Orphanet: ORPHA331226]
Tyrosine kinase 2 deficiency
OMIM: 611521
Orphanet: ORPHA331226
Disease:  Juvenile rheumatoid factor-negative polyarthritis
Orphanet: ORPHA85408
Disease:  Oligoarticular juvenile arthritis
Orphanet: ORPHA85410

References

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2. Anastassiadis T, Deacon SW, Devarajan K, Ma H, Peterson JR. (2011) Comprehensive assay of kinase catalytic activity reveals features of kinase inhibitor selectivity. Nat Biotechnol, 29 (11): 1039-45. [PMID:22037377]

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9. Chrencik JE, Patny A, Leung IK, Korniski B, Emmons TL, Hall T, Weinberg RA, Gormley JA, Williams JM, Day JE et al.. (2010) Structural and thermodynamic characterization of the TYK2 and JAK3 kinase domains in complex with CP-690550 and CMP-6. J Mol Biol, 400 (3): 413-33. [PMID:20478313]

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11. Coffey G, Betz A, DeGuzman F, Pak Y, Inagaki M, Baker DC, Hollenbach SJ, Pandey A, Sinha U. (2014) The novel kinase inhibitor PRT062070 (Cerdulatinib) demonstrates efficacy in models of autoimmunity and B-cell cancer. J Pharmacol Exp Ther, 351 (3): 538-48. [PMID:25253883]

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How to cite this page

Janus kinase (JakA) family: tyrosine kinase 2. Last modified on 18/04/2023. Accessed on 10/06/2023. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2269.