Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTLXE1TX)

• DOT Name: Delta-like protein 3 (DLL3)
• Synonyms: Drosophila Delta homolog 3; Delta3
• Gene Name: DLL3
• Related Disease:
  Spondylocostal dysostosis 1, autosomal recessive
  Autosomal recessive spondylocostal dysostosis
• UniProt ID: DLL3_HUMAN
• Pfam ID: PF00008 ; PF12661 ; PF07657
• Sequence:
  MVSPRMSGLLSQTVILALIFLPQTRPAGVFELQIHSFGPGPGPGAPRSPCSARLPCRLFF
  RVCLKPGLSEEAAESPCALGAALSARGPVYTEQPGAPAPDLPLPDGLLQVPFRDAWPGTF
  SFIIETWREELGDQIGGPAWSLLARVAGRRRLAAGGPWARDIQRAGAWELRFSYRARCEP
  PAVGTACTRLCRPRSAPSRCGPGLRPCAPLEDECEAPLVCRAGCSPEHGFCEQPGECRCL
  EGWTGPLCTVPVSTSSCLSPRGPSSATTGCLVPGPGPCDGNPCANGGSCSETPRSFECTC
  PRGFYGLRCEVSGVTCADGPCFNGGLCVGGADPDSAYICHCPPGFQGSNCEKRVDRCSLQ
  PCRNGGLCLDLGHALRCRCRAGFAGPRCEHDLDDCAGRACANGGTCVEGGGAHRCSCALG
  FGGRDCRERADPCAARPCAHGGRCYAHFSGLVCACAPGYMGARCEFPVHPDGASALPAAP
  PGLRPGDPQRYLLPPALGLLVAAGVAGAALLLVHVRRRGHSQDAGSRLLAGTPEPSVHAL
  PDALNNLRTQEGSGDGPSSSVDWNRPEDVDPQGIYVISAPSIYAREVATPLFPPLHTGRA
  GQRQHLLFPYPSSILSVK
• Function: Inhibits primary neurogenesis. May be required to divert neurons along a specific differentiation pathway. Plays a role in the formation of somite boundaries during segmentation of the paraxial mesoderm.
• KEGG Pathway:
  Endocrine resistance (hsa01522)
  Notch sig.ling pathway (hsa04330)
  Th1 and Th2 cell differentiation (hsa04658)
  Pathways in cancer (hsa05200)
  Chemical carcinogenesis - receptor activation (hsa05207)
  Breast cancer (hsa05224)
• Reactome Pathway:
  Somitogenesis (R-HSA-9824272)
  Formation of paraxial mesoderm (R-HSA-9793380)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Spondylocostal dysostosis 1, autosomal recessive	DIS96K65	Definitive	Autosomal recessive	[1]
Autosomal recessive spondylocostal dysostosis	DISAJI27	Supportive	Autosomal recessive	[2]

4 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 Delta-like protein 3 (DLL3).	[3]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Delta-like protein 3 (DLL3).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Delta-like protein 3 (DLL3).	[10]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the methylation of Delta-like protein 3 (DLL3).	[11]

6 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 Delta-like protein 3 (DLL3).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin affects the expression of Delta-like protein 3 (DLL3).	[5]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of Delta-like protein 3 (DLL3).	[6]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Delta-like protein 3 (DLL3).	[8]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Delta-like protein 3 (DLL3).	[9]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Delta-like protein 3 (DLL3).	[5]

References

• [1] Mutations in the human delta homologue, DLL3, cause axial skeletal defects in spondylocostal dysostosis. Nat Genet. 2000 Apr;24(4):438-41. doi: 10.1038/74307.
• [2] Spondylocostal Dysostosis, Autosomal Recessive. 2009 Aug 25 [updated 2023 Aug 17]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(?) [Internet]. Seattle (WA): University of Washington, Seattle; 1993C2024.
• [3] 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.
• [4] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [5] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [6] Identification of novel low-dose bisphenol a targets in human foreskin fibroblast cells derived from hypospadias patients. PLoS One. 2012;7(5):e36711. doi: 10.1371/journal.pone.0036711. Epub 2012 May 4.
• [7] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [8] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [9] Minimal peroxide exposure of neuronal cells induces multifaceted adaptive responses. PLoS One. 2010 Dec 17;5(12):e14352. doi: 10.1371/journal.pone.0014352.
• [10] 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.
• [11] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.