Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTYO99HC)

• DOT Name: Interleukin-23 subunit alpha (IL23A)
• Synonyms: IL-23 subunit alpha; IL-23-A; Interleukin-23 subunit p19; IL-23p19
• Gene Name: IL23A
• UniProt ID: IL23A_HUMAN
• PDB ID: 3D85; 3D87; 3DUH; 3QWR; 4GRW; 5MJ3; 5MJ4; 5MXA; 5MZV; 5NJD; 6UIB; 6WDQ
• Pfam ID: PF16649
• Sequence:
  MLGSRAVMLLLLLPWTAQGRAVPGGSSPAWTQCQQLSQKLCTLAWSAHPLVGHMDLREEG
  DEETTNDVPHIQCGDGCDPQGLRDNSQFCLQRIHQGLIFYEKLLGSDIFTGEPSLLPDSP
  VGQLHASLLGLSQLLQPEGHHWETQQIPSLSPSQPWQRLLLRFKILRSLQAFVAVAARVF
  AHGAATLSP
• Function: Associates with IL12B to form the pro-inflammatory cytokine IL-23 that plays different roles in innate and adaptive immunity. Released by antigen-presenting cells such as dendritic cells or macrophages, binds to a heterodimeric receptor complex composed of IL12RB1 and IL23R to activate JAK2 and TYK2 which then phosphorylate the receptor to form a docking site leading to the phosphorylation of STAT3 and STAT4. This process leads to activation of several pathways including p38 MAPK or NF-kappa-B and promotes the production of pro-inflammatory cytokines such as interleukin-17A/IL17A. In turn, participates in the early and effective intracellular bacterial clearance. Promotes the expansion and survival of T-helper 17 cells, a CD4-positive helper T-cell subset that produces IL-17, as well as other IL-17-producing cells.
• Tissue Specificity: Secreted by activated dendritic and phagocytic cells and keratinocytes. Also expressed by dermal Langerhans cells (at protein level).
• KEGG Pathway:
  Cytokine-cytokine receptor interaction (hsa04060)
  C-type lectin receptor sig.ling pathway (hsa04625)
  JAK-STAT sig.ling pathway (hsa04630)
  Th17 cell differentiation (hsa04659)
  Pertussis (hsa05133)
  Tuberculosis (hsa05152)
  Pathways in cancer (hsa05200)
  Inflammatory bowel disease (hsa05321)
  Rheumatoid arthritis (hsa05323)
• Reactome Pathway:
  Interleukin-23 signaling (R-HSA-9020933)
  Interleukin-4 and Interleukin-13 signaling (R-HSA-6785807)

Molecular Interaction Atlas (MIA) of This DOT

21 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Interleukin-23 subunit alpha (IL23A).	[1]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Interleukin-23 subunit alpha (IL23A).	[2]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Interleukin-23 subunit alpha (IL23A).	[3]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Interleukin-23 subunit alpha (IL23A).	[4]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Interleukin-23 subunit alpha (IL23A).	[5]
Bortezomib	DMNO38U	Approved	Bortezomib increases the expression of Interleukin-23 subunit alpha (IL23A).	[6]
Azathioprine	DMMZSXQ	Approved	Azathioprine decreases the expression of Interleukin-23 subunit alpha (IL23A).	[4]
Diclofenac	DMPIHLS	Approved	Diclofenac decreases the expression of Interleukin-23 subunit alpha (IL23A).	[4]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of Interleukin-23 subunit alpha (IL23A).	[4]
Malathion	DMXZ84M	Approved	Malathion increases the expression of Interleukin-23 subunit alpha (IL23A).	[7]
Simvastatin	DM30SGU	Approved	Simvastatin decreases the expression of Interleukin-23 subunit alpha (IL23A).	[8]
Prednisolone	DMQ8FR2	Approved	Prednisolone decreases the expression of Interleukin-23 subunit alpha (IL23A).	[4]
Methylprednisolone	DM4BDON	Approved	Methylprednisolone decreases the expression of Interleukin-23 subunit alpha (IL23A).	[4]
Dinoprostone	DMTYOPD	Approved	Dinoprostone increases the expression of Interleukin-23 subunit alpha (IL23A).	[9]
Misoprostol	DMHVJFK	Approved	Misoprostol increases the expression of Interleukin-23 subunit alpha (IL23A).	[9]
Apilimod dimesylate	DM4N2O0	Phase 2	Apilimod dimesylate decreases the expression of Interleukin-23 subunit alpha (IL23A).	[10]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Interleukin-23 subunit alpha (IL23A).	[12]
BUTAPROST	DMVYNJZ	Patented	BUTAPROST increases the expression of Interleukin-23 subunit alpha (IL23A).	[9]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Interleukin-23 subunit alpha (IL23A).	[13]
Phencyclidine	DMQBEYX	Investigative	Phencyclidine decreases the expression of Interleukin-23 subunit alpha (IL23A).	[14]
Phorbol 12,13-butyrate	DMZWTY7	Investigative	Phorbol 12,13-butyrate increases the expression of Interleukin-23 subunit alpha (IL23A).	[15]

1 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Interleukin-23 subunit alpha (IL23A).	[11]

References

• [1] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [2] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [3] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [4] Antirheumatic drug response signatures in human chondrocytes: potential molecular targets to stimulate cartilage regeneration. Arthritis Res Ther. 2009;11(1):R15.
• [5] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [6] Induction of heme oxygenase-1 by cobalt protoporphyrin enhances the antitumour effect of bortezomib in adult T-cell leukaemia cells. Br J Cancer. 2007 Oct 22;97(8):1099-105. doi: 10.1038/sj.bjc.6604003. Epub 2007 Sep 25.
• [7] Exposure to Insecticides Modifies Gene Expression and DNA Methylation in Hematopoietic Tissues In Vitro. Int J Mol Sci. 2023 Mar 26;24(7):6259. doi: 10.3390/ijms24076259.
• [8] Simvastatin inhibits IL-17 secretion by targeting multiple IL-17-regulatory cytokines and by inhibiting the expression of IL-17 transcription factor RORC in CD4+ lymphocytes. J Immunol. 2008 May 15;180(10):6988-96. doi: 10.4049/jimmunol.180.10.6988.
• [9] Prostaglandin E2 regulates Th17 cell differentiation and function through cyclic AMP and EP2/EP4 receptor signaling. J Exp Med. 2009 Mar 16;206(3):535-48. doi: 10.1084/jem.20082293. Epub 2009 Mar 9.
• [10] New interleukin-23 pathway inhibitors in dermatology: ustekinumab, briakinumab, and secukinumab. Am J Clin Dermatol. 2011 Apr 1;12(2):113-25. doi: 10.2165/11538950-000000000-00000.
• [11] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [12] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [13] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [14] Microarray Analysis of Gene Expression Alteration in Human Middle Ear Epithelial Cells Induced by Asian Sand Dust. Clin Exp Otorhinolaryngol. 2015 Dec;8(4):345-53. doi: 10.3342/ceo.2015.8.4.345. Epub 2015 Nov 10.
• [15] Expression and regulation of interleukin-23 subunits in human peripheral blood mononuclear cells and hematopoietic cell lines in response to various inducers. Cell Biol Int. 2004;28(10):689-97. doi: 10.1016/j.cellbi.2004.07.002.