Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT81X593)

• DOT Name: Cell adhesion molecule-related/down-regulated by oncogenes (CDON)
• Gene Name: CDON
• Related Disease:
  Bacteremia
  Chronic renal failure
  Holoprosencephaly 11
  Coloboma
  Gastrointestinal stromal tumour
  Hypopituitarism
  Prostate cancer
  Prostate carcinoma
  Pituitary stalk interruption syndrome
  Holoprosencephaly
• UniProt ID: CDON_HUMAN
• PDB ID: 3D1M; 3N1F; 3N1Q
• Pfam ID: PF00041 ; PF07679 ; PF13927
• Sequence:
  MHPDLGPLCTLLYVTLTILCSSVSSDLAPYFTSEPLSAVQKLGGPVVLHCSAQPVTTRIS
  WLHNGKTLDGNLEHVKIHQGTLTILSLNSSLLGYYQCLANNSIGAIVSGPATVSVAVLGD
  FGSSTKHVITAEEKSAGFIGCRVPESNPKAEVRYKIRGKWLEHSTENYLILPSGNLQILN
  VSLEDKGSYKCAAYNPVTHQLKVEPIGRKLLVSRPSSDDVHILHPTHSQALAVLSRSPVT
  LECVVSGVPAPQVYWLKDGQDIAPGSNWRRLYSHLATDSVDPADSGNYSCMAGNKSGDVK
  YVTYMVNVLEHASISKGLQDQIVSLGATVHFTCDVHGNPAPNCTWFHNAQPIHPSARHLT
  AGNGLKISGVTVEDVGMYQCVADNGIGFMHSTGRLEIENDGGFKPVIITAPVSAKVADGD
  FVTLSCNASGLPVPVIRWYDSHGLITSHPSQVLRSKSRKSQLSRPEGLNLEPVYFVLSQA
  GASSLHIQAVTQEHAGKYICEAANEHGTTQAEASLMVVPFETNTKAETVTLPDAAQNDDR
  SKRDGSETGLLSSFPVKVHPSAVESAPEKNASGISVPDAPIILSPPQTHTPDTYNLVWRA
  GKDGGLPINAYFVKYRKLDDGVGMLGSWHTVRVPGSENELHLAELEPSSLYEVLMVARSA
  AGEGQPAMLTFRTSKEKTASSKNTQASSPPVGIPKYPVVSEAANNNFGVVLTDSSRHSGV
  PEAPDRPTISTASETSVYVTWIPRANGGSPITAFKVEYKRMRTSNWLVAAEDIPPSKLSV
  EVRSLEPGSTYKFRVIAINHYGESFRSSASRPYQVVGFPNRFSSRPITGPHIAYTEAVSD
  TQIMLKWTYIPSSNNNTPIQGFYIYYRPTDSDNDSDYKRDVVEGSKQWHMIGHLQPETSY
  DIKMQCFNEGGESEFSNVMICETKVKRVPGASEYPVKDLSTPPNSLGSGGNVGPATSPAR
  SSDMLYLIVGCVLGVMVLILMVFIAMCLWKNRQQNTIQKYDPPGYLYQGSDMNGQMVDYT
  TLSGASQINGNVHGGFLTNGGLSSGYSHLHHKVPNAVNGIVNGSLNGGLYSGHSNSLTRT
  HVDFEHPHHLVNGGGMYTAVPQIDPLECVNCRNCRNNNRCFTKTNSTFSSSPPPVVPVVA
  PYPQDGLEMKPLSHVKVPVCLTSAVPDCGQLPEESVKDNVEPVPTQRTCCQDIVNDVSSD
  GSEDPAEFSRGQEGMINLRIPDHLQLAKSCVWEGDSCAHSETEINIVSWNALILPPVPEG
  CAEKTMWSPPGIPLDSPTEVLQQPRET
• Function: Component of a cell-surface receptor complex that mediates cell-cell interactions between muscle precursor cells. Promotes differentiation of myogenic cells.
• KEGG Pathway: Hedgehog sig.ling pathway (hsa04340)
• Reactome Pathway:
  Ligand-receptor interactions (R-HSA-5632681)
  Activation of SMO (R-HSA-5635838)
  Myogenesis (R-HSA-525793)

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Bacteremia	DIS6N9RZ	Definitive	Biomarker	[1]
Chronic renal failure	DISGG7K6	Definitive	Genetic Variation	[2]
Holoprosencephaly 11	DIS6U5EL	Definitive	Autosomal dominant	[3]
Coloboma	DISP39N5	Strong	Biomarker	[4]
Gastrointestinal stromal tumour	DIS6TJYS	Strong	Biomarker	[5]
Hypopituitarism	DIS1QT3G	Strong	Genetic Variation	[6]
Prostate cancer	DISF190Y	moderate	Altered Expression	[7]
Prostate carcinoma	DISMJPLE	moderate	Altered Expression	[7]
Pituitary stalk interruption syndrome	DISGSN5T	Supportive	Autosomal dominant	[8]
Holoprosencephaly	DISR35EC	Limited	Biomarker	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Cell adhesion molecule-related/down-regulated by oncogenes (CDON).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Cell adhesion molecule-related/down-regulated by oncogenes (CDON).	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Cell adhesion molecule-related/down-regulated by oncogenes (CDON).	[10]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Cell adhesion molecule-related/down-regulated by oncogenes (CDON).	[11]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of Cell adhesion molecule-related/down-regulated by oncogenes (CDON).	[12]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Cell adhesion molecule-related/down-regulated by oncogenes (CDON).	[13]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Cell adhesion molecule-related/down-regulated by oncogenes (CDON).	[14]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Cell adhesion molecule-related/down-regulated by oncogenes (CDON).	[15]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Cell adhesion molecule-related/down-regulated by oncogenes (CDON).	[16]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Cell adhesion molecule-related/down-regulated by oncogenes (CDON).	[13]
Irinotecan	DMP6SC2	Approved	Irinotecan decreases the expression of Cell adhesion molecule-related/down-regulated by oncogenes (CDON).	[17]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Cell adhesion molecule-related/down-regulated by oncogenes (CDON).	[18]
Epigallocatechin gallate	DMCGWBJ	Phase 3	Epigallocatechin gallate increases the expression of Cell adhesion molecule-related/down-regulated by oncogenes (CDON).	[19]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Cell adhesion molecule-related/down-regulated by oncogenes (CDON).	[21]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Cell adhesion molecule-related/down-regulated by oncogenes (CDON).	[22]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Cell adhesion molecule-related/down-regulated by oncogenes (CDON).	[23]

References

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• [2] Genetics of Chronic Kidney Disease Stages Across Ancestries: The PAGE Study.Front Genet. 2019 May 24;10:494. doi: 10.3389/fgene.2019.00494. eCollection 2019.
• [3] Mutations in CDON, encoding a hedgehog receptor, result in holoprosencephaly and defective interactions with other hedgehog receptors. Am J Hum Genet. 2011 Aug 12;89(2):231-40. doi: 10.1016/j.ajhg.2011.07.001. Epub 2011 Jul 28.
• [4] Homozygous variants in MAPRE2 and CDON in individual with skin folds, growth delay, retinal coloboma, and pyloric stenosis.Am J Med Genet A. 2019 Dec;179(12):2454-2458. doi: 10.1002/ajmg.a.61355. Epub 2019 Sep 9.
• [5] Hedgehog pathway dysregulation contributes to the pathogenesis of human gastrointestinal stromal tumors via GLI-mediated activation of KIT expression. Oncotarget. 2016 Nov 29;7(48):78226-78241. doi: 10.18632/oncotarget.12909.
• [6] Classical and non-classical causes of GH deficiency in the paediatric age.Best Pract Res Clin Endocrinol Metab. 2016 Dec;30(6):705-736. doi: 10.1016/j.beem.2016.11.008. Epub 2016 Nov 24.
• [7] Identification of transmembrane protein in prostate cancer by the Escherichia coli ampicillin secretion trap: expression of CDON is involved in tumor cell growth and invasion.Pathobiology. 2011;78(5):277-84. doi: 10.1159/000329588. Epub 2011 Aug 17.
• [8] A Nonsense Mutation in the Hedgehog Receptor CDON Associated With Pituitary Stalk Interruption Syndrome. J Clin Endocrinol Metab. 2016 Jan;101(1):12-5. doi: 10.1210/jc.2015-2995. Epub 2015 Nov 3.
• [9] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [10] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [11] 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.
• [12] Estradiol and selective estrogen receptor modulators differentially regulate target genes with estrogen receptors alpha and beta. Mol Biol Cell. 2004 Mar;15(3):1262-72. doi: 10.1091/mbc.e03-06-0360. Epub 2003 Dec 29.
• [13] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [14] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [15] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [16] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [17] Clinical determinants of response to irinotecan-based therapy derived from cell line models. Clin Cancer Res. 2008 Oct 15;14(20):6647-55.
• [18] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [19] Application of the adverse outcome pathway concept for investigating developmental neurotoxicity potential of Chinese herbal medicines by using human neural progenitor cells in vitro. Cell Biol Toxicol. 2023 Feb;39(1):319-343. doi: 10.1007/s10565-022-09730-4. Epub 2022 Jun 15.
• [20] 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.
• [21] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [22] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [23] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.