Target Information
| Target General Information | Top | |||||
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| Target ID |
T78932
(Former ID: TTDNC00412)
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| Target Name |
TYK2 tyrosine kinase (TYK2)
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| Synonyms |
Non-receptor tyrosine-protein kinase TYK2
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| Gene Name |
TYK2
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| Target Type |
Successful target
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[1] | ||||
| Disease | [+] 1 Target-related Diseases | + | ||||
| 1 | Psoriasis [ICD-11: EA90] | |||||
| 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.
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| BioChemical Class |
Kinase
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| UniProt ID | ||||||
| EC Number |
EC 2.7.10.2
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| Sequence |
MPLRHWGMARGSKPVGDGAQPMAAMGGLKVLLHWAGPGGGEPWVTFSESSLTAEEVCIHI
AHKVGITPPCFNLFALFDAQAQVWLPPNHILEIPRDASLMLYFRIRFYFRNWHGMNPREP AVYRCGPPGTEASSDQTAQGMQLLDPASFEYLFEQGKHEFVNDVASLWELSTEEEIHHFK NESLGMAFLHLCHLALRHGIPLEEVAKKTSFKDCIPRSFRRHIRQHSALTRLRLRNVFRR FLRDFQPGRLSQQMVMVKYLATLERLAPRFGTERVPVCHLRLLAQAEGEPCYIRDSGVAP TDPGPESAAGPPTHEVLVTGTGGIQWWPVEEEVNKEEGSSGSSGRNPQASLFGKKAKAHK AVGQPADRPREPLWAYFCDFRDITHVVLKEHCVSIHRQDNKCLELSLPSRAAALSFVSLV DGYFRLTADSSHYLCHEVAPPRLVMSIRDGIHGPLLEPFVQAKLRPEDGLYLIHWSTSHP YRLILTVAQRSQAPDGMQSLRLRKFPIEQQDGAFVLEGWGRSFPSVRELGAALQGCLLRA GDDCFSLRRCCLPQPGETSNLIIMRGARASPRTLNLSQLSFHRVDQKEITQLSHLGQGTR TNVYEGRLRVEGSGDPEEGKMDDEDPLVPGRDRGQELRVVLKVLDPSHHDIALAFYETAS LMSQVSHTHLAFVHGVCVRGPENIMVTEYVEHGPLDVWLRRERGHVPMAWKMVVAQQLAS ALSYLENKNLVHGNVCGRNILLARLGLAEGTSPFIKLSDPGVGLGALSREERVERIPWLA PECLPGGANSLSTAMDKWGFGATLLEICFDGEAPLQSRSPSEKEHFYQRQHRLPEPSCPQ LATLTSQCLTYEPTQRPSFRTILRDLTRLQPHNLADVLTVNPDSPASDPTVFHKRYLKKI RDLGEGHFGKVSLYCYDPTNDGTGEMVAVKALKADCGPQHRSGWKQEIDILRTLYHEHII KYKGCCEDQGEKSLQLVMEYVPLGSLRDYLPRHSIGLAQLLLFAQQICEGMAYLHAQHYI HRDLAARNVLLDNDRLVKIGDFGLAKAVPEGHEYYRVREDGDSPVFWYAPECLKEYKFYY ASDVWSFGVTLYELLTHCDSSQSPPTKFLELIGIAQGQMTVLRLTELLERGERLPRPDKC PCEVYHLMKNCWETEASFRPTFENLIPILKTVHEKYQGQAPSVFSVC Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | AlphaFold | ||||
| Drugs and Modes of Action | Top | |||||
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| Approved Drug(s) | [+] 1 Approved Drugs | + | ||||
| 1 | Deucravacitinib | Drug Info | Approved | Plaque psoriasis | [2] | |
| Clinical Trial Drug(s) | [+] 1 Clinical Trial Drugs | + | ||||
| 1 | PF-06826647 | Drug Info | Phase 1 | Plaque psoriasis | [1] | |
| Mode of Action | [+] 1 Modes of Action | + | ||||
| Inhibitor | [+] 30 Inhibitor drugs | + | ||||
| 1 | Deucravacitinib | Drug Info | [1] | |||
| 2 | PF-06826647 | Drug Info | [1] | |||
| 3 | Aminooxazole carboxamide derivative 1 | Drug Info | [5] | |||
| 4 | Aminopyridine derivative 1 | Drug Info | [5] | |||
| 5 | Aminopyrimidine derivative 5 | Drug Info | [5] | |||
| 6 | Aminotriazolopyridine derivative 1 | Drug Info | [6] | |||
| 7 | Benzimidazole derivative 7 | Drug Info | [6] | |||
| 8 | Bis-aminopyrimidine derivative 1 | Drug Info | [6] | |||
| 9 | Bis-aminopyrimidine derivative 2 | Drug Info | [6] | |||
| 10 | Bis-aminopyrimidine derivative 3 | Drug Info | [6] | |||
| 11 | Bis-aminopyrimidine derivative 4 | Drug Info | [6] | |||
| 12 | Bis-aminopyrimidine derivative 5 | Drug Info | [6] | |||
| 13 | Imidazopyridine derivative 3 | Drug Info | [5] | |||
| 14 | Imidazo[4,5-c]pyridine derivative 1 | Drug Info | [6] | |||
| 15 | PMID27774822-Compound-Figure11Example5 | Drug Info | [5] | |||
| 16 | PMID27774822-Compound-Figure3CompoundI-165 | Drug Info | [5] | |||
| 17 | PMID27774822-Compound-Figure9Example15 | Drug Info | [5] | |||
| 18 | PMID27774824-Compound-Figure3Example18 | Drug Info | [6] | |||
| 19 | PMID27774824-Compound-Figure6Example12 | Drug Info | [6] | |||
| 20 | PMID27774824-Compound-Figure9Example2down | Drug Info | [6] | |||
| 21 | Pyrazolopyridine derivative 3 | Drug Info | [5] | |||
| 22 | Pyrazolopyridine derivative 5 | Drug Info | [5] | |||
| 23 | Pyrazolo[4,3-c]pyridine derivative 2 | Drug Info | [6] | |||
| 24 | Pyrrolo-pyridone derivative 3 | Drug Info | [5] | |||
| 25 | Pyrrolo[2,3-d]pyrimidine derivative 6 | Drug Info | [5] | |||
| 26 | Pyrrolo[2,3-d]pyrimidine derivative 8 | Drug Info | [5] | |||
| 27 | Tricyclic compound 11 | Drug Info | [5] | |||
| 28 | Tricyclic heterocycle derivative 5 | Drug Info | [5] | |||
| 29 | Tricyclic pyrrolopyridine compound 1 | Drug Info | [5] | |||
| 30 | CMP-6 | Drug Info | [7] | |||
| Cell-based Target Expression Variations | Top | |||||
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| Cell-based Target Expression Variations | ||||||
| Drug Binding Sites of Target | Top | |||||
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| Ligand Name: Tofacitinib | Ligand Info | |||||
| Structure Description | Structural and Thermodynamic Characterization of the TYK2 and JAK3 Kinase Domains in Complex with CP-690550 and CMP-6 | PDB:3LXN | ||||
| Method | X-ray diffraction | Resolution | 2.50 Å | Mutation | Yes | [8] |
| PDB Sequence |
DPTVFHKRYL
897 KKIRDLGEGH907 FGKVSLYCYD917 PTNDGTGEMV927 AVKALKADAG937 PQHRSGWKQE 947 IDILRTLYHE957 HIIKYKGCCE967 DAGAASLQLV977 MEYVPLGSLR987 DYLPRHSIGL 997 AQLLLFAQQI1007 CEGMAYLHAQ1017 HYIHRDLAAR1027 NVLLDNDRLV1037 KIGDFGLAKA 1047 VPEGHEYRVG1061 DSPVFWYAPE1071 CLKEYKFYYA1081 SDVWSFGVTL1091 YELLTHCDSS 1101 QSPPTKFLEL1111 IGIAQGQMTV1121 LRLTELLERG1131 ERLPRPDKCP1141 AEVYHLMKNC 1151 WETEASFRPT1161 FENLIPILKT1171 VHEKYQG
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LEU903
3.564
GLY904
3.155
GLU905
3.118
GLY906
2.858
HIS907
4.235
GLY909
3.149
LYS910
3.980
VAL911
3.227
ALA928
3.214
LYS930
3.598
ILE960
3.737
MET978
4.020
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| Ligand Name: ASP-015K | Ligand Info | |||||
| Structure Description | Crystal structure of TYK2 in complex with peficitinib | PDB:6AAM | ||||
| Method | X-ray diffraction | Resolution | 1.98 Å | Mutation | Yes | [9] |
| PDB Sequence |
DPTVFHKRYL
897 KKIRDLGGKV911 SLYCYDPTNT923 GEMVAVKALD935 AGPQHRSGWK945 QEIDILRTLY 955 HEHIIKYKGC965 CEDAGAASLQ975 LVMEYVPLGS985 LRDYLPRHSI995 GLAQLLLFAQ 1005 QICEGMAYLH1015 AQHYIHRNLA1025 ARNVLLDNDR1035 LVKIGDFGLA1045 KAVPPVFWYA 1069 PECLKEYKFY1079 YASDVWSFGV1089 TLYELLTHCD1099 SSQSPPTKFL1109 ELIGLAQGQM 1119 TVLRLTELLE1129 RGERLPRPDK1139 CPAEVYHLMK1149 NCWETEASFR1159 PTFENLIPIL 1169 KTVHEKYQG
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| Click to View More Binding Site Information of This Target with Different Ligands | ||||||
| Different Human System Profiles of Target | Top |
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Human Similarity Proteins
of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target.
A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs
(Brief Bioinform, 21: 649-662, 2020).
Human Tissue Distribution
of target is determined from a proteomics study that quantified more than 12,000 genes across 32 normal human tissues. Tissue Specificity (TS) score was used to define the enrichment of target across tissues.
The distribution of targets among different tissues or organs need to be taken into consideration when assessing the target druggability, as it is generally accepted that the wider the target distribution, the greater the concern over potential adverse effects
(Nat Rev Drug Discov, 20: 64-81, 2021).
Human Pathway Affiliation
of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function.
Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes
(Pharmacol Rev, 58: 259-279, 2006).
Biological Network Descriptors
of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database.
The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information
(Front Pharmacol, 9, 1245, 2018;
Curr Opin Struct Biol. 44:134-142, 2017).
Human Similarity Proteins
Human Tissue Distribution
Human Pathway Affiliation
Biological Network Descriptors
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Note:
If a protein has TS (tissue specficity) scores at least in one tissue >= 2.5, this protein is called tissue-enriched (including tissue-enriched-but-not-specific and tissue-specific). In the plots, the vertical lines are at thresholds 2.5 and 4.
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| KEGG Pathway | Pathway ID | Affiliated Target | Pathway Map |
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| Necroptosis | hsa04217 | Affiliated Target |
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| Class: Cellular Processes => Cell growth and death | Pathway Hierarchy | ||
| Osteoclast differentiation | hsa04380 | Affiliated Target |
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| Class: Organismal Systems => Development and regeneration | Pathway Hierarchy | ||
| NOD-like receptor signaling pathway | hsa04621 | Affiliated Target |
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| Class: Organismal Systems => Immune system | Pathway Hierarchy | ||
| JAK-STAT signaling pathway | hsa04630 | Affiliated Target |
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| Class: Environmental Information Processing => Signal transduction | Pathway Hierarchy | ||
| Th1 and Th2 cell differentiation | hsa04658 | Affiliated Target |
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| Class: Organismal Systems => Immune system | Pathway Hierarchy | ||
| Th17 cell differentiation | hsa04659 | Affiliated Target |
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| Class: Organismal Systems => Immune system | Pathway Hierarchy | ||
| Click to Show/Hide the Information of Affiliated Human Pathways | |||
| Degree | 23 | Degree centrality | 2.47E-03 | Betweenness centrality | 1.77E-04 |
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| Closeness centrality | 2.29E-01 | Radiality | 1.40E+01 | Clustering coefficient | 2.29E-01 |
| Neighborhood connectivity | 3.15E+01 | Topological coefficient | 1.03E-01 | Eccentricity | 11 |
| Download | Click to Download the Full PPI Network of This Target | ||||
| Chemical Structure based Activity Landscape of Target | Top |
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| Drug Property Profile of Target | Top | |
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| (1) Molecular Weight (mw) based Drug Clustering | (2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering | |
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| (3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering | (4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering | |
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| (5) Rotatable Bond Count (rotbonds) based Drug Clustering | (6) Topological Polar Surface Area (polararea) based Drug Clustering | |
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| "RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five | ||
| Co-Targets | Top | |||||
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| Co-Targets | ||||||
| Target Poor or Non Binders | Top | |||||
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| Target Poor or Non Binders | ||||||
| Target Regulators | Top | |||||
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| Target-interacting Proteins | ||||||
| Target Affiliated Biological Pathways | Top | |||||
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| KEGG Pathway | [+] 8 KEGG Pathways | + | ||||
| 1 | Osteoclast differentiation | |||||
| 2 | Jak-STAT signaling pathway | |||||
| 3 | Toxoplasmosis | |||||
| 4 | Hepatitis C | |||||
| 5 | Measles | |||||
| 6 | Influenza A | |||||
| 7 | Herpes simplex infection | |||||
| 8 | Epstein-Barr virus infection | |||||
| PID Pathway | [+] 5 PID Pathways | + | ||||
| 1 | IL27-mediated signaling events | |||||
| 2 | Signaling events mediated by PTP1B | |||||
| 3 | IL12-mediated signaling events | |||||
| 4 | IL6-mediated signaling events | |||||
| 5 | IL23-mediated signaling events | |||||
| Reactome | [+] 5 Reactome Pathways | + | ||||
| 1 | Interleukin-6 signaling | |||||
| 2 | MAPK3 (ERK1) activation | |||||
| 3 | MAPK1 (ERK2) activation | |||||
| 4 | Interferon alpha/beta signaling | |||||
| 5 | Regulation of IFNA signaling | |||||
| WikiPathways | [+] 7 WikiPathways | + | ||||
| 1 | Interferon type I signaling pathways | |||||
| 2 | IL-4 Signaling Pathway | |||||
| 3 | IL-6 signaling pathway | |||||
| 4 | Oncostatin M Signaling Pathway | |||||
| 5 | Interleukin-11 Signaling Pathway | |||||
| 6 | Type III interferon signaling | |||||
| 7 | Interferon alpha/beta signaling | |||||
| References | Top | |||||
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| REF 1 | Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA) | |||||
| REF 2 | FDA Approved Drug Products from FDA Official Website. 2022. Application Number: 214958. | |||||
| REF 3 | ClinicalTrials.gov (NCT03210961) A First in Human Study to Evaluate Safety, Tolerability, and Pharmacology of PF-06826647 in Healthy Subjects and Subjects With Plaque Psoriasis. U.S. National Institutes of Health. | |||||
| REF 4 | ClinicalTrials.gov (NCT05153148) A Phase 2b, Randomized, Multi-Center, Double-Blind, Placebo-Controlled, Multiple Dose Study to Evaluate the Efficacy, Safety, and Tolerability of NDI-034858 in Subjects With Active Psoriatic Arthritis. U.S.National Institutes of Health. | |||||
| REF 5 | Inhibitors of JAK-family kinases: an update on the patent literature 2013-2015, part 2.Expert Opin Ther Pat. 2017 Feb;27(2):145-161. | |||||
| REF 6 | Inhibitors of JAK-family kinases: an update on the patent literature 2013-2015, part 1.Expert Opin Ther Pat. 2017 Feb;27(2):127-143. | |||||
| REF 7 | A systematic interaction map of validated kinase inhibitors with Ser/Thr kinases. Proc Natl Acad Sci U S A. 2007 Dec 18;104(51):20523-8. | |||||
| REF 8 | Structural and thermodynamic characterization of the TYK2 and JAK3 kinase domains in complex with CP-690550 and CMP-6. J Mol Biol. 2010 Jul 16;400(3):413-33. | |||||
| REF 9 | Discovery and structural characterization of peficitinib (ASP015K) as a novel and potent JAK inhibitor. Bioorg Med Chem. 2018 Oct 1;26(18):4971-4983. | |||||
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