Target Information
Target General Information | Top | |||||
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Target ID |
T23666
(Former ID: TTDI02013)
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Target Name |
Aryl hydrocarbon receptor (AHR)
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Synonyms |
bHLHe76; Class E basic helixloophelix protein 76; Class E basic helix-loop-helix protein 76; AhR; Ah receptor
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Gene Name |
AHR
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Target Type |
Successful target
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[1] | ||||
Disease | [+] 2 Target-related Diseases | + | ||||
1 | Psoriasis [ICD-11: EA90] | |||||
2 | Thrombocytopenia [ICD-11: 3B64] | |||||
Function |
Binds to the XRE promoter region of genes it activates. Activates the expression of multiple phase I and II xenobiotic chemical metabolizing enzyme genes (such as the CYP1A1 gene). Mediates biochemical and toxic effects of halogenated aromatic hydrocarbons. Involved in cell-cycle regulation. Likely to play an important role in the development and maturation of many tissues. Regulates the circadian clock by inhibiting the basal and circadian expression of the core circadian component PER1. Inhibits PER1 by repressing the CLOCK-ARNTL/BMAL1 heterodimer mediated transcriptional activation of PER1. The heterodimer ARNT:AHR binds to core DNA sequence 5'-TGCGTG-3' within the dioxin response element (DRE) of target gene promoters and activates their transcription. Ligand-activated transcriptional activator.
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UniProt ID | ||||||
Sequence |
MNSSSANITYASRKRRKPVQKTVKPIPAEGIKSNPSKRHRDRLNTELDRLASLLPFPQDV
INKLDKLSVLRLSVSYLRAKSFFDVALKSSPTERNGGQDNCRAANFREGLNLQEGEFLLQ ALNGFVLVVTTDALVFYASSTIQDYLGFQQSDVIHQSVYELIHTEDRAEFQRQLHWALNP SQCTESGQGIEEATGLPQTVVCYNPDQIPPENSPLMERCFICRLRCLLDNSSGFLAMNFQ GKLKYLHGQKKKGKDGSILPPQLALFAIATPLQPPSILEIRTKNFIFRTKHKLDFTPIGC DAKGRIVLGYTEAELCTRGSGYQFIHAADMLYCAESHIRMIKTGESGMIVFRLLTKNNRW TWVQSNARLLYKNGRPDYIIVTQRPLTDEEGTEHLRKRNTKLPFMFTTGEAVLYEATNPF PAIMDPLPLRTKNGTSGKDSATTSTLSKDSLNPSSLLAAMMQQDESIYLYPASSTSSTAP FENNFFNESMNECRNWQDNTAPMGNDTILKHEQIDQPQDVNSFAGGHPGLFQDSKNSDLY SIMKNLGIDFEDIRHMQNEKFFRNDFSGEVDFRDIDLTDEILTYVQDSLSKSPFIPSDYQ QQQSLALNSSCMVQEHLHLEQQQQHHQKQVVVEPQQQLCQKMKHMQVNGMFENWNSNQFV PFNCPQQDPQQYNVFTDLHGISQEFPYKSEMDSMPYTQNFISCNQPVLPQHSKCTELDYP MGSFEPSPYPTTSSLEDFVTCLQLPENQKHGLNPQSAIITPQTCYAGAVSMYQCQPEPQH THVGQMQYNPVLPGQQAFLNKFQNGVLNETYPAELNNINNTQTTTHLQPLHHPSEARPFP DLTSSGFL Click to Show/Hide
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3D Structure | Click to Show 3D Structure of This Target | AlphaFold | ||||
HIT2.0 ID | T84W8G |
Drugs and Modes of Action | Top | |||||
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Approved Drug(s) | [+] 2 Approved Drugs | + | ||||
1 | Romiplostim | Drug Info | Approved | Thrombocytopenia | [2], [3] | |
2 | Tapinarof | Drug Info | Approved | Plaque psoriasis | [4] | |
Clinical Trial Drug(s) | [+] 4 Clinical Trial Drugs | + | ||||
1 | RVT-505 | Drug Info | Phase 2 | Atopic dermatitis | [5] | |
2 | BAY 2416964 | Drug Info | Phase 1 | Solid tumour/cancer | [6] | |
3 | IK-175 | Drug Info | Phase 1 | Urothelial carcinoma | [7] | |
4 | AT-177 | Drug Info | Clinical trial | Ulcerative colitis | [8] | |
Preclinical Drug(s) | [+] 2 Preclinical Drugs | + | ||||
1 | 2-(1H-indole-3,-carbonyl)-thiazole-4-carboxylic acid methyl ester | Drug Info | Preclinical | Glioma | [9] | |
2 | CB7993113 | Drug Info | Preclinical | Solid tumour/cancer | [10] | |
Mode of Action | [+] 3 Modes of Action | + | ||||
Modulator | [+] 2 Modulator drugs | + | ||||
1 | Romiplostim | Drug Info | [1], [11] | |||
2 | RVT-505 | Drug Info | [5] | |||
Agonist | [+] 4 Agonist drugs | + | ||||
1 | Tapinarof | Drug Info | [4] | |||
2 | AT-177 | Drug Info | [8] | |||
3 | 2-(1H-indole-3,-carbonyl)-thiazole-4-carboxylic acid methyl ester | Drug Info | [9] | |||
4 | 6-Formylindolo[3,2-b]carbazole | Drug Info | [14] | |||
Antagonist | [+] 4 Antagonist drugs | + | ||||
1 | BAY 2416964 | Drug Info | [6] | |||
2 | IK-175 | Drug Info | [12] | |||
3 | CB7993113 | Drug Info | [13] | |||
4 | CH-223191 | Drug Info | [15] |
Cell-based Target Expression Variations | Top | |||||
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Cell-based Target Expression Variations |
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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There is no similarity protein (E value < 0.005) for this target
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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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Th17 cell differentiation | hsa04659 | Affiliated Target |
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Class: Organismal Systems => Immune system | Pathway Hierarchy |
Degree | 14 | Degree centrality | 1.50E-03 | Betweenness centrality | 1.16E-03 |
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Closeness centrality | 2.47E-01 | Radiality | 1.43E+01 | Clustering coefficient | 1.65E-01 |
Neighborhood connectivity | 4.80E+01 | Topological coefficient | 1.00E-01 | Eccentricity | 10 |
Download | Click to Download the Full PPI Network of This Target | ||||
Chemical Structure based Activity Landscape of Target | Top |
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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-regulating microRNAs | ||||||
Target-interacting Proteins |
References | Top | |||||
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REF 1 | A Phase I study of the angiogenesis inhibitor SU5416 (semaxanib) in solid tumours, incorporating dynamic contrast MR pharmacodynamic end points. Br J Cancer. 2005 Oct 17;93(8):876-83. | |||||
REF 2 | URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 6974). | |||||
REF 3 | 2008 FDA drug approvals. Nat Rev Drug Discov. 2009 Feb;8(2):93-6. | |||||
REF 4 | FDA Approved Drug Products from FDA Official Website. 2022. Application Number: 215272. | |||||
REF 5 | Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA) | |||||
REF 6 | ClinicalTrials.gov (NCT04069026) A First-in-Humans Dose Finding Study for an Aryl Hydrocarbon Receptor Inhibitor (AhRi) in Patients With Advanced Cancer. U.S. National Institutes of Health. | |||||
REF 7 | ClinicalTrials.gov (NCT04200963) A Phase 1a/b Study of IK-175 as a Single Agent and in Combination With Nivolumab in Patients With Locally Advanced or Metastatic Solid Tumors and Urothelial Carcinoma. U.S. National Institutes of Health. | |||||
REF 8 | Clinical pipeline report, company report or official report of Azora Therapeutics | |||||
REF 9 | 1'H-Indole-3'-Carbonyl-Thiazole-4-Carboxylic Acid Methyl Ester Blocked Human Glioma Cell Invasion via Aryl Hydrocarbon Receptor's Regulation of Cytoskeletal Contraction. Biomed Res Int. 2020 Oct 3;2020:2616930. | |||||
REF 10 | Tryptophan metabolism as a common therapeutic target in cancer, neurodegeneration and beyond. Nat Rev Drug Discov. 2019 May;18(5):379-401. | |||||
REF 11 | SU5416, a VEGF Receptor Inhibitor and Ligand of the AHR, Represents a New Alternative for Immunomodulation | |||||
REF 12 | Clinical pipeline report, company report or official report of Ikena Oncology. | |||||
REF 13 | In silico identification of an aryl hydrocarbon receptor antagonist with biological activity in vitro and in vivo. Mol Pharmacol. 2014 Nov;86(5):593-608. | |||||
REF 14 | 6-Formylindolo(3,2-b)carbazole induced aryl hydrocarbon receptor activation prevents intestinal barrier dysfunction through regulation of claudin-2 expression. Chem Biol Interact. 2018 May 25;288:83-90. | |||||
REF 15 | Novel compound 2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazo-phenyl)-amide (CH-223191) prevents 2,3,7,8-TCDD-induced toxicity by antagonizing the aryl hydrocarbon receptor. Mol Pharmacol. 2006 Jun;69(6):1871-8. |
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