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Target has curated data in GtoImmuPdb
Target id: 2269
Nomenclature: tyrosine kinase 2
Abbreviated Name: Tyk2
Family: Janus kinase (JakA) family
Gene and Protein Information | ||||||
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 |
JTK1 |
Database Links | |
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 | |||||||||||||
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Enzyme Reaction | ||||
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Download all structure-activity data for this target as a CSV file
Inhibitors | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Inhibitor Comments | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
The IC50 for decernotinib vs. TYK2 is >10 μM [10]. |
Allosteric Modulators | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Other Binding Ligands | |||||||||||||||||||||||||||||||||||||||||||||||||||
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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: 13,52 |
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Target used in screen: TYK2(JH1domain-catalytic) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Target used in screen: TYK2(JH2domain-pseudokinase) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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 |
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Target used in screen: nd/TYK2 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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 [43]. 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 [23,36]. TYK2 selectivity has been achieved by targeting the protein's pseudokinase (Jak homology 2 or JH2) domain [30,47], 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 [40], 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 | ||
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Clinically-Relevant Mutations and Pathophysiology | ||||||||||||
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29. Liu C, Lin J, Langevine C, Smith D, Li J, Tokarski JS, Khan J, Ruzanov M, Strnad J, Zupa-Fernandez A et al.. (2021) Discovery of BMS-986202: A Clinical Tyk2 Inhibitor that Binds to Tyk2 JH2. J Med Chem, 64 (1): 677-694. [PMID:33370104]
30. 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]
31. Long DD, Smith C, Thompson C. (2020) DIMETHYL AMINO AZETIDINE AMIDES AS JAK INHIBITORS. Patent number: WO/2020/051105. Assignee: THERAVANCE BIOPHARMA. Priority date: 04/09/2018. Publication date: 12/03/2020.
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Janus kinase (JakA) family: tyrosine kinase 2. Last modified on 13/08/2024. Accessed on 03/11/2024. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetoimmunopharmacology.org/GRAC/ObjectDisplayForward?objectId=2269.