tyrosine kinase 2 | Janus kinase (JakA) family | IUPHAR/BPS Guide to PHARMACOLOGY

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tyrosine kinase 2

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
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 1187 19p13.2 TYK2 tyrosine kinase 2
Mouse - 1207 9 A3 Tyk2 tyrosine kinase 2
Rat - 1186 8q13 Tyk2 tyrosine kinase 2
Previous and Unofficial Names
JTK1
Database Links
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
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:  34
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:  7
Image of receptor 3D structure from RCSB PDB
Description:  Tyk2 with compound 23
PDB Id:  6DBM
Ligand:  brepocitinib
Resolution:  2.368Å
Species:  Human
References:  13
Enzyme Reaction
EC Number: 2.7.10.2

Download all structure-activity data for this target as a CSV file

Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
izencitinib Hs Inhibition 9.0 – 10.0 pKi 18
⤷ pKi 9.0 – 10.0 (Ki 1x10-9 – 1x10-10 M) [18]
delgocitinib Hs Inhibition 7.8 pKi 32
⤷ pKi 7.8 (Ki 1.4x10-8 M) [32]
Description: In an assay using the kinase domain of the recombinant human enzyme, a biotinylated peptide substrate, and [33P]ATP.
cerdulatinib Hs Inhibition 9.3 pIC50 9
⤷ pIC50 9.3 (IC50 5x10-10 M) [9]
JAK inhibitor I Hs Inhibition 9.0 pIC50 12
⤷ pIC50 9.0 (IC50 1x10-9 M) [12]
SAR-20347 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] Hs Inhibition 8.4 pIC50 25
⤷ pIC50 8.4 (IC50 4x10-9 M) [25]
Description: Measuring binding to the JH2 pseudokinase domain of human TYK2.
ruxolitinib Hs Inhibition 7.5 – 9.3 pIC50 8,16
⤷ pIC50 9.3 (IC50 5.5x10-10 M) [16]
pIC50 7.5 (IC50 3x10-8 M) [8]
peficitinib Hs Inhibition 8.3 pIC50 20
⤷ pIC50 8.3 (IC50 5x10-9 M) [20]
example 1 [WO2018112379A1] Hs Inhibition 8.1 pIC50 22
⤷ pIC50 8.1 (IC50 7.4x10-9 M) [22]
Description: Determined in a biochemical high-throughput mass spectrometry (HTMS) assay.
TG02 Hs Inhibition 7.8 pIC50 14
⤷ pIC50 7.8 (IC50 1.4x10-8 M) [14]
ilginatinib Hs Inhibition 7.7 pIC50 27
⤷ pIC50 7.7 (IC50 2.2x10-8 M) [27]
brepocitinib Hs Inhibition 7.6 pIC50 13
⤷ pIC50 7.6 (IC50 2.3x10-8 M) [13]
PF-06263276 Hs Inhibition 7.5 pIC50 21
⤷ pIC50 7.5 (IC50 2.97x10-8 M) [21]
JAK inhibitor 17b Hs Inhibition 7.4 pIC50 11
⤷ pIC50 7.4 (IC50 3.94x10-8 M) [11]
baricitinib Hs Inhibition 7.2 pIC50 8
⤷ pIC50 7.2 (IC50 6.1x10-8 M) [8]
BMS-911543 Hs Inhibition 7.2 pIC50 29
⤷ pIC50 7.2 (IC50 6.6x10-8 M) [29]
JAK inhibitor 20a Hs Inhibition 7.1 pIC50 11
⤷ pIC50 7.1 (IC50 7.37x10-8 M) [11]
oclacitinib Hs Inhibition 7.1 pIC50 4
⤷ pIC50 7.1 (IC50 7.51x10-8 M) [4]
LASW1393 Hs Inhibition 6.9 pIC50 3
⤷ pIC50 6.9 (IC50 1.3x10-7 M) [3]
PF-956980 Hs Inhibition 6.9 pIC50 15
⤷ pIC50 6.9 (IC50 1.28x10-7 M) [15]
fedratinib Hs Inhibition 6.8 pIC50 24
⤷ pIC50 6.8 (IC50 1.5x10-7 M) [24]
solcitinib Hs Inhibition 6.7 pIC50 5
⤷ pIC50 6.7 (IC50 2.19x10-7 M) [5]
tofacitinib Hs Inhibition 6.3 pIC50 8
⤷ pIC50 6.3 (IC50 4.89x10-7 M) [8]
Description: In a biochemical enzyme assay.
filgotinib Hs Inhibition 5.6 – 6.9 pIC50 8,35
⤷ pIC50 6.9 (IC50 1.16x10-7 M) [35]
pIC50 5.6 (IC50 2.6x10-6 M) [8]
AZD4205 Hs Inhibition 5.6 pIC50 31
⤷ pIC50 5.6 (IC50 2.8x10-6 M) [31]
Description: Inhbition of TYK2 enzymatic activity.
upadacitinib Hs Inhibition 5.3 pIC50 36
⤷ pIC50 5.3 (IC50 4.7x10-6 M) [36]
JAK3 inhibitor 32 Hs Inhibition <5.0 pIC50 6
⤷ pIC50 <5.0 (IC50 >1x10-5 M) [6]
JAK3 inhibitor 34 Hs Inhibition <5.0 pIC50 6
⤷ pIC50 <5.0 (IC50 >1x10-5 M) [6]
Inhibitor Comments
The IC50 for decernotinib vs. TYK2 is >10 μM [8].
Allosteric Modulators
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
BMS-986165 Hs Inhibition 10.7 pKi 38
⤷ pKi 10.7 (Ki 2x10-11 M) [38]
Description: Determined in a Morrison titration by varying the concentration of the fluorescent probe in the TYK2 JH2 assay.
BMS-986165 Hs Inhibition 9.7 pIC50 38
⤷ pIC50 9.7 (IC50 2x10-10 M) [38]
Description: Binding to TYK2's JH2 pseudokinase domain in a biochemical binding assay.
DiscoveRx KINOMEscan® screen
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: 10,37
Key to terms and symbols Click column headers to sort
Target used in screen: TYK2(JH1domain-catalytic)
Ligand Sp. Type Action Value Parameter
ruxolitinib Hs Inhibitor Inhibition 9.1 pKd
tofacitinib Hs Inhibitor Inhibition 8.3 pKd
JNJ-28312141 Hs Inhibitor Inhibition 8.2 pKd
lestaurtinib Hs Inhibitor Inhibition 7.8 pKd
fedratinib Hs Inhibitor Inhibition 7.7 pKd
staurosporine Hs Inhibitor Inhibition 7.3 pKd
NVP-TAE684 Hs Inhibitor Inhibition 7.1 pKd
dovitinib Hs Inhibitor Inhibition 6.8 pKd
KW-2449 Hs Inhibitor Inhibition 6.8 pKd
alvocidib Hs Inhibitor Inhibition 6.7 pKd
Target used in screen: TYK2(JH2domain-pseudokinase)
Ligand Sp. Type Action Value Parameter
alvocidib Hs Inhibitor Inhibition 7.5 pKd
dasatinib Hs Inhibitor Inhibition 7.0 pKd
sunitinib Hs Inhibitor Inhibition 6.4 pKd
fedratinib Hs Inhibitor Inhibition 6.3 pKd
JNJ-28312141 Hs Inhibitor Inhibition 6.3 pKd
MLN-120B Hs Inhibitor Inhibition 6.3 pKd
KW-2449 Hs Inhibitor Inhibition 6.3 pKd
SU-14813 Hs Inhibitor Inhibition 6.1 pKd
TG-100-115 Hs Inhibitor Inhibition 6.1 pKd
lestaurtinib 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
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 Hs Inhibitor Inhibition 0.9
K-252a Hs Inhibitor Inhibition 0.9
JAK inhibitor I Hs Inhibitor Inhibition 1.5
staurosporine Hs Inhibitor Inhibition 1.9
Gö 6976 Hs Inhibitor Inhibition 2.6
SB 218078 Hs Inhibitor Inhibition 4.3
Cdk2 inhibitor IV Hs Inhibitor Inhibition 5.0
Cdk1/2 inhibitor III Hs Inhibitor Inhibition 5.1
IKK-2 inhibitor IV Hs Inhibitor Inhibition 6.3
midostaurin 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 [30]. 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 [19] 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 [17,26]. TYK2 selectivity has been achieved by targeting the protein's pseudokinase (Jak homology 2 or JH2) domain [23,33], 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 BMS-986165, which is an orally active compound that has progressed to Phase 3 clinical evaluation in patients with psoriasis [28]. 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. As of June 2019 the chemical structure of BMS-986165 has not been formally disclosed.
Immuno Process Associations
Immuno Process:  Inflammation
GO Annotations:  Associated to 1 GO processes
GO:0060337 type I interferon signaling pathway TAS
Immuno Process:  Cytokine production & signalling
GO Annotations:  Associated to 5 GO processes
GO:0019221 cytokine-mediated signaling pathway TAS
GO:0035722 interleukin-12-mediated signaling pathway TAS
GO:0038155 interleukin-23-mediated signaling pathway TAS
GO:0060337 type I interferon signaling pathway TAS
GO:0070106 interleukin-27-mediated signaling pathway TAS
Clinically-Relevant Mutations and Pathophysiology
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. 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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13. Fensome A, Ambler CM, Arnold E, Banker ME, Brown MF, Chrencik J, Clark JD, Dowty ME, Efremov IV, Flick A et al.. (2018) Dual Inhibition of TYK2 and JAK1 for the Treatment of Autoimmune Diseases: Discovery of (( S)-2,2-Difluorocyclopropyl)((1 R,5 S)-3-(2-((1-methyl-1 H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone (PF-06700841). J. Med. Chem., 61 (19): 8597-8612. [PMID:30113844]

14. Goh KC, Novotny-Diermayr V, Hart S, Ong LC, Loh YK, Cheong A, Tan YC, Hu C, Jayaraman R, William AD et al.. (2012) TG02, a novel oral multi-kinase inhibitor of CDKs, JAK2 and FLT3 with potent anti-leukemic properties. Leukemia, 26 (2): 236-43. [PMID:21860433]

15. Hanan EJ, Liang J, Wang X, Blake R, Blaquiere N, Staben ST. (2020) Monomeric targeted protein degraders. J. Med. Chem., [Epub ahead of print]. DOI: 10.1021/acs.jmedchem.0c00093 [PMID:32352776]

16. Hanan EJ, van Abbema A, Barrett K, Blair WS, Blaney J, Chang C, Eigenbrot C, Flynn S, Gibbons P, Hurley CA et al.. (2012) Discovery of potent and selective pyrazolopyrimidine janus kinase 2 inhibitors. J. Med. Chem., 55 (22): 10090-107. [PMID:23061660]

17. He X, Chen X, Zhang H, Xie T, Ye XY. (2019) Selective Tyk2 inhibitors as potential therapeutic agents: a patent review (2015-2018). Expert Opin Ther Pat, 29 (2): 137-149. [PMID:30621465]

18. Hudson R, Kozak J, Fatheree PR, Podesto DD, Brandt GEL, Fleury M, Beausoleil A-M, Huang X, Thalladi VR. (2016) Naphthyridine compounds as jak kinase inhibitors. Patent number: WO2016191524A1. Assignee: Theravance Biopharma R&D. Priority date: 28/05/2015. Publication date: 01/12/2016.

19. Ishizaki M, Muromoto R, Akimoto T, Sekine Y, Kon S, Diwan M, Maeda H, Togi S, Shimoda K, Oritani K et al.. (2014) Tyk2 is a therapeutic target for psoriasis-like skin inflammation. Int. Immunol., 26 (5): 257-67. [PMID:24345760]

20. Ito M, Yamazaki S, Yamagami K, Kuno M, Morita Y, Okuma K, Nakamura K, Chida N, Inami M, Inoue T et al.. (2017) A novel JAK inhibitor, peficitinib, demonstrates potent efficacy in a rat adjuvant-induced arthritis model. J. Pharmacol. Sci., 133 (1): 25-33. [PMID:28117214]

21. Jones P, Storer RI, Sabnis YA, Wakenhut FM, Whitlock GA, England KS, Mukaiyama T, Dehnhardt CM, Coe JW, Kortum SW et al.. (2017) Design and Synthesis of a Pan-Janus Kinase Inhibitor Clinical Candidate (PF-06263276) Suitable for Inhaled and Topical Delivery for the Treatment of Inflammatory Diseases of the Lungs and Skin. J. Med. Chem., 60 (2): 767-786. [PMID:27983835]

22. Koudriakova T, Kreutter K, Leonard K, Rizzolio M, Smith RC, Tichenor MS, Wang A. (2018) Small molecule inhibitors of the JAK family of kinases. Patent number: WO2018112379A1. Assignee: Janssen Pharmaceutica. Priority date: 16/12/2016. Publication date: 21/06/2018.

23. Liu C, Lin J, Moslin R, Tokarski JS, Muckelbauer J, Chang C, Tredup J, Xie D, Park H, Li P et al.. (2019) Identification of Imidazo[1,2-b]pyridazine Derivatives as Potent, Selective, and Orally Active Tyk2 JH2 Inhibitors. ACS Med Chem Lett, 10 (3): 383-388. [PMID:30891145]

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32. Tanimoto A, Ogawa Y, Oki C, Kimoto Y, Nozawa K, Amano W, Noji S, Shiozaki M, Matsuo A, Shinozaki Y et al.. (2015) Pharmacological properties of JTE-052: a novel potent JAK inhibitor that suppresses various inflammatory responses in vitro and in vivo. Inflamm. Res., 64 (1): 41-51. [PMID:25387665]

33. Tokarski JS, Zupa-Fernandez A, Tredup JA, Pike K, Chang C, Xie D, Cheng L, Pedicord D, Muckelbauer J, Johnson SR et al.. (2015) Tyrosine Kinase 2-mediated Signal Transduction in T Lymphocytes Is Blocked by Pharmacological Stabilization of Its Pseudokinase Domain. J. Biol. Chem., 290 (17): 11061-74. [PMID:25762719]

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35. Van Rompaey L, Galien R, van der Aar EM, Clement-Lacroix P, Nelles L, Smets B, Lepescheux L, Christophe T, Conrath K, Vandeghinste N et al.. (2013) Preclinical characterization of GLPG0634, a selective inhibitor of JAK1, for the treatment of inflammatory diseases. J. Immunol., 191 (7): 3568-77. [PMID:24006460]

36. Voss JW, Camp HS, Padley RJ. (2015) Jak1 selective inhibitor and uses thereof. Patent number: WO2015061665. Assignee: Abbvie Inc.. Priority date: 24/10/2013. Publication date: 30/04/2015.

37. Wodicka LM, Ciceri P, Davis MI, Hunt JP, Floyd M, Salerno S, Hua XH, Ford JM, Armstrong RC, Zarrinkar PP et al.. (2010) Activation state-dependent binding of small molecule kinase inhibitors: structural insights from biochemistry. Chem. Biol., 17 (11): 1241-9. [PMID:21095574]

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How to cite this page

Janus kinase (JakA) family: tyrosine kinase 2. Last modified on 16/06/2020. Accessed on 24/09/2020. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2269.