Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTX7JL8H)

• DOT Name: Leucine-rich repeat-containing protein 15 (LRRC15)
• Synonyms: Leucine-rich repeat protein induced by beta-amyloid homolog; hLib
• Gene Name: LRRC15
• Related Disease:
  Alzheimer disease
  Malignant soft tissue neoplasm
  Neoplasm
  Sarcoma
  Fetal growth restriction
  Osteoarthritis
  Advanced cancer
• UniProt ID: LRC15_HUMAN
• Pfam ID: PF00560 ; PF13855
• Sequence:
  MPLKHYLLLLVGCQAWGAGLAYHGCPSECTCSRASQVECTGARIVAVPTPLPWNAMSLQI
  LNTHITELNESPFLNISALIALRIEKNELSRITPGAFRNLGSLRYLSLANNKLQVLPIGL
  FQGLDSLESLLLSSNQLLQIQPAHFSQCSNLKELQLHGNHLEYIPDGAFDHLVGLTKLNL
  GKNSLTHISPRVFQHLGNLQVLRLYENRLTDIPMGTFDGLVNLQELALQQNQIGLLSPGL
  FHNNHNLQRLYLSNNHISQLPPSVFMQLPQLNRLTLFGNSLKELSPGIFGPMPNLRELWL
  YDNHISSLPDNVFSNLRQLQVLILSRNQISFISPGAFNGLTELRELSLHTNALQDLDGNV
  FRMLANLQNISLQNNRLRQLPGNIFANVNGLMAIQLQNNQLENLPLGIFDHLGKLCELRL
  YDNPWRCDSDILPLRNWLLLNQPRLGTDTVPVCFSPANVRGQSLIIINVNVAVPSVHVPE
  VPSYPETPWYPDTPSYPDTTSVSSTTELTSPVEDYTDLTTIQVTDDRSVWGMTQAQSGLA
  IAAIVIGIVALACSLAACVGCCCCKKRSQAVLMQMKAPNEC
• Function: (Microbial infection) Modulates the ability of SARS-CoV-2 to infect host cells through interaction with the spike protein. Does not act as a SARS-CoV-2 entry receptor but sequesters virions and antagonizes in trans SARS-CoV-2 infection of ACE2(+) cells when expressed on nearby cells.
• Tissue Specificity: Expressed in brain and placenta . Expressed in lung fibroblasts . Expressed in chodrocytes .

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Alzheimer disease	DISF8S70	Strong	Biomarker	[1]
Malignant soft tissue neoplasm	DISTC6NO	Strong	Altered Expression	[2]
Neoplasm	DISZKGEW	Strong	Biomarker	[3]
Sarcoma	DISZDG3U	Strong	Altered Expression	[2]
Fetal growth restriction	DIS5WEJ5	moderate	Genetic Variation	[4]
Osteoarthritis	DIS05URM	moderate	Genetic Variation	[5]
Advanced cancer	DISAT1Z9	Limited	Altered Expression	[3]

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 Leucine-rich repeat-containing protein 15 (LRRC15).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Leucine-rich repeat-containing protein 15 (LRRC15).	[7]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Leucine-rich repeat-containing protein 15 (LRRC15).	[8]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Leucine-rich repeat-containing protein 15 (LRRC15).	[9]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Leucine-rich repeat-containing protein 15 (LRRC15).	[10]
Capecitabine	DMTS85L	Approved	Capecitabine decreases the expression of Leucine-rich repeat-containing protein 15 (LRRC15).	[11]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Leucine-rich repeat-containing protein 15 (LRRC15).	[12]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Leucine-rich repeat-containing protein 15 (LRRC15).	[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 increases the methylation of Leucine-rich repeat-containing protein 15 (LRRC15).	[14]

References

• [1] Lib, transcriptionally induced in senile plaque-associated astrocytes, promotes glial migration through extracellular matrix.Biochem Biophys Res Commun. 2005 Sep 23;335(2):631-6. doi: 10.1016/j.bbrc.2005.07.117.
• [2] LRRC15 Is a Novel Mesenchymal Protein and Stromal Target for Antibody-Drug Conjugates.Cancer Res. 2018 Jul 15;78(14):4059-4072. doi: 10.1158/0008-5472.CAN-18-0327. Epub 2018 May 15.
• [3] Single-Cell RNA Sequencing Reveals Stromal Evolution into LRRC15(+) Myofibroblasts as a Determinant of Patient Response to Cancer Immunotherapy.Cancer Discov. 2020 Feb;10(2):232-253. doi: 10.1158/2159-8290.CD-19-0644. Epub 2019 Nov 7.
• [4] Intrauterine growth retardation-associated syncytin b hypermethylation in maternal rat blood revealed by DNA methylation array analysis.Pediatr Res. 2017 Oct;82(4):704-711. doi: 10.1038/pr.2017.137. Epub 2017 Jul 5.
• [5] Systematic Analysis of Transcriptomic Profile of Chondrocytes in Osteoarthritic Knee Using Next-Generation Sequencing and Bioinformatics.J Clin Med. 2018 Dec 10;7(12):535. doi: 10.3390/jcm7120535.
• [6] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [7] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [8] 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.
• [9] 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.
• [10] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [11] Gene expression responses reflecting 5-FU-induced toxicity: Comparison between patient colon tissue and 3D human colon organoids. Toxicol Lett. 2022 Dec 1;371:17-24. doi: 10.1016/j.toxlet.2022.09.013. Epub 2022 Sep 29.
• [12] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [13] Quantitative proteomics and transcriptomics addressing the estrogen receptor subtype-mediated effects in T47D breast cancer cells exposed to the phytoestrogen genistein. Mol Cell Proteomics. 2011 Jan;10(1):M110.002170.
• [14] 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.