Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TT037IE)

• DTT Name: Aryl hydrocarbon receptor (AHR)
• Synonyms: bHLHe76; Class E basic helixloophelix protein 76; Class E basic helix-loop-helix protein 76; AhR; Ah receptor
• Gene Name: AHR
• DTT Type: Successful target; [1]
• Related Disease: Thrombocytopenia [ICD-11: 3B64]
• UniProt ID: AHR_HUMAN
• TTD ID: T23666
• Sequence:
  MNSSSANITYASRKRRKPVQKTVKPIPAEGIKSNPSKRHRDRLNTELDRLASLLPFPQDV
  INKLDKLSVLRLSVSYLRAKSFFDVALKSSPTERNGGQDNCRAANFREGLNLQEGEFLLQ
  ALNGFVLVVTTDALVFYASSTIQDYLGFQQSDVIHQSVYELIHTEDRAEFQRQLHWALNP
  SQCTESGQGIEEATGLPQTVVCYNPDQIPPENSPLMERCFICRLRCLLDNSSGFLAMNFQ
  GKLKYLHGQKKKGKDGSILPPQLALFAIATPLQPPSILEIRTKNFIFRTKHKLDFTPIGC
  DAKGRIVLGYTEAELCTRGSGYQFIHAADMLYCAESHIRMIKTGESGMIVFRLLTKNNRW
  TWVQSNARLLYKNGRPDYIIVTQRPLTDEEGTEHLRKRNTKLPFMFTTGEAVLYEATNPF
  PAIMDPLPLRTKNGTSGKDSATTSTLSKDSLNPSSLLAAMMQQDESIYLYPASSTSSTAP
  FENNFFNESMNECRNWQDNTAPMGNDTILKHEQIDQPQDVNSFAGGHPGLFQDSKNSDLY
  SIMKNLGIDFEDIRHMQNEKFFRNDFSGEVDFRDIDLTDEILTYVQDSLSKSPFIPSDYQ
  QQQSLALNSSCMVQEHLHLEQQQQHHQKQVVVEPQQQLCQKMKHMQVNGMFENWNSNQFV
  PFNCPQQDPQQYNVFTDLHGISQEFPYKSEMDSMPYTQNFISCNQPVLPQHSKCTELDYP
  MGSFEPSPYPTTSSLEDFVTCLQLPENQKHGLNPQSAIITPQTCYAGAVSMYQCQPEPQH
  THVGQMQYNPVLPGQQAFLNKFQNGVLNETYPAELNNINNTQTTTHLQPLHHPSEARPFP
  DLTSSGFL
• 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.
• KEGG Pathway:
  Th17 cell differentiation (hsa04659)
  Cushing syndrome (hsa04934)
  Chemical carcinogenesis - receptor activation (hsa05207)
  Chemical carcinogenesis - reactive oxygen species (hsa05208)
• Reactome Pathway:
  Phase I - Functionalization of compounds (R-HSA-211945)
  Endogenous sterols (R-HSA-211976)
  Xenobiotics (R-HSA-211981)
  Aryl hydrocarbon receptor signalling (R-HSA-8937144)
  PPARA activates gene expression (R-HSA-1989781)

Molecular Interaction Atlas (MIA) of This DTT

1 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Romiplostim	DM3U7SZ	Thrombocytopenia	3B64	Approved	[1], [2]

3 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
RVT-505	DM3C9F8	Atopic dermatitis	EA80	Phase 2	[3]
BAY 2416964	DMD9N12	Solid tumour/cancer	2A00-2F9Z	Phase 1	[4]
IK-175	DMDU54Y	Urothelial carcinoma	2C92.0	Phase 1	[5]

2 Preclinical Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
2-(1H-indole-3,-carbonyl)-thiazole-4-carboxylic acid methyl ester	DMIS1G7	Glioma	2A00.0	Preclinical	[6]
CB7993113	DMJUQ6E	Solid tumour/cancer	2A00-2F9Z	Preclinical	[7]

2 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
6-Formylindolo[3,2-b]carbazole	DMN84RM	Dermatitis	EA80-EA89	Investigative	[8]
CH-223191	DMMJZYC	Solid tumour/cancer	2A00-2F9Z	Investigative	[9]

References

• [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.
• [2] SU5416, a VEGF Receptor Inhibitor and Ligand of the AHR, Represents a New Alternative for Immunomodulation
• [3] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [4] 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.
• [5] Clinical pipeline report, company report or official report of Ikena Oncology.
• [6] 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.
• [7] 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.
• [8] 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.
• [9] 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.