Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTLR2PYX)

• DOT Name: Ly6/PLAUR domain-containing protein 3 (LYPD3)
• Synonyms: GPI-anchored metastasis-associated protein C4.4A homolog; Matrigel-induced gene C4 protein; MIG-C4
• Gene Name: LYPD3
• Related Disease:
  Advanced cancer
  Colorectal neoplasm
  Lung neoplasm
  Neoplasm
  Non-small-cell lung cancer
  Squamous cell carcinoma
• UniProt ID: LYPD3_HUMAN
• PDB ID: 6IOM; 6ION
• Pfam ID: PF00021
• Sequence:
  MDPARKAGAQAMIWTAGWLLLLLLRGGAQALECYSCVQKADDGCSPNKMKTVKCAPGVDV
  CTEAVGAVETIHGQFSLAVRGCGSGLPGKNDRGLDLHGLLAFIQLQQCAQDRCNAKLNLT
  SRALDPAGNESAYPPNGVECYSCVGLSREACQGTSPPVVSCYNASDHVYKGCFDGNVTLT
  AANVTVSLPVRGCVQDEFCTRDGVTGPGFTLSGSCCQGSRCNSDLRNKTYFSPRIPPLVR
  LPPPEPTTVASTTSVTTSTSAPVRPTSTTKPMPAPTSQTPRQGVEHEASRDEEPRLTGGA
  AGHQDRSNSGQYPAKGGPQQPHNKGCVAPTAGLAALLLAVAAGVLL
• Function: Supports cell migration. May be involved in urothelial cell-matrix interactions. May be involved in tumor progression.
• Tissue Specificity: Expressed in placenta, skin and urothelium. Found in suprabasal keratinocytes of chronic wounds. Weak expression is found in esophagus and peripheral blood mononuclear cells. Found in the majority of primary and metastatic transitional cell carcinomas (TCCs) and as well in breast cancer tissues, but not in adjacent normal tissues. High expression is found in the tumor component of some noninvasive superficial lesions and in invasive and metastatic urothelial cancers.
• Reactome Pathway: Post-translational modification (R-HSA-163125)

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Colorectal neoplasm	DISR1UCN	Strong	Biomarker	[2]
Lung neoplasm	DISVARNB	Strong	Altered Expression	[3]
Neoplasm	DISZKGEW	Strong	Biomarker	[4]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[5]
Squamous cell carcinoma	DISQVIFL	Strong	Altered Expression	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Ly6/PLAUR domain-containing protein 3 (LYPD3).	[6]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Ly6/PLAUR domain-containing protein 3 (LYPD3).	[7]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Ly6/PLAUR domain-containing protein 3 (LYPD3).	[8]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Ly6/PLAUR domain-containing protein 3 (LYPD3).	[9]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Ly6/PLAUR domain-containing protein 3 (LYPD3).	[10]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Ly6/PLAUR domain-containing protein 3 (LYPD3).	[11]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Ly6/PLAUR domain-containing protein 3 (LYPD3).	[10]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Ly6/PLAUR domain-containing protein 3 (LYPD3).	[13]

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 Ly6/PLAUR domain-containing protein 3 (LYPD3).	[12]

References

• [1] Preclinical Antitumor Efficacy of BAY 1129980-a Novel Auristatin-Based Anti-C4.4A (LYPD3) Antibody-Drug Conjugate for the Treatment of Non-Small Cell Lung Cancer.Mol Cancer Ther. 2017 May;16(5):893-904. doi: 10.1158/1535-7163.MCT-16-0474. Epub 2017 Mar 14.
• [2] C4.4A as a candidate marker in the diagnosis of colorectal cancer.Br J Cancer. 2007 Oct 22;97(8):1146-56. doi: 10.1038/sj.bjc.6604012. Epub 2007 Oct 2.
• [3] Tumour cell expression of C4.4A, a structural homologue of the urokinase receptor, correlates with poor prognosis in non-small cell lung cancer.Lung Cancer. 2007 Nov;58(2):260-6. doi: 10.1016/j.lungcan.2007.06.025. Epub 2007 Aug 13.
• [4] The Lineage Determining Factor GRHL2 Collaborates with FOXA1 to Establish a Targetable Pathway in Endocrine Therapy-Resistant Breast Cancer.Cell Rep. 2019 Oct 22;29(4):889-903.e10. doi: 10.1016/j.celrep.2019.09.032.
• [5] Long non-coding RNA OGFRP1 regulates LYPD3 expression by sponging miR-124-3p and promotes non-small cell lung cancer progression.Biochem Biophys Res Commun. 2018 Oct 28;505(2):578-585. doi: 10.1016/j.bbrc.2018.09.146. Epub 2018 Sep 28.
• [6] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [7] Retinoic acid receptor alpha amplifications and retinoic acid sensitivity in breast cancers. Clin Breast Cancer. 2013 Oct;13(5):401-8.
• [8] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [9] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [10] 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.
• [11] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [12] 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.
• [13] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.