Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTYOFT3K)

• DOT Name: Lysophosphatidic acid receptor 3 (LPAR3)
• Synonyms: LPA receptor 3; LPA-3; Lysophosphatidic acid receptor Edg-7
• Gene Name: LPAR3
• UniProt ID: LPAR3_HUMAN
• Pfam ID: PF00001
• Sequence:
  MNECHYDKHMDFFYNRSNTDTVDDWTGTKLVIVLCVGTFFCLFIFFSNSLVIAAVIKNRK
  FHFPFYYLLANLAAADFFAGIAYVFLMFNTGPVSKTLTVNRWFLRQGLLDSSLTASLTNL
  LVIAVERHMSIMRMRVHSNLTKKRVTLLILLVWAIAIFMGAVPTLGWNCLCNISACSSLA
  PIYSRSYLVFWTVSNLMAFLIMVVVYLRIYVYVKRKTNVLSPHTSGSISRRRTPMKLMKT
  VMTVLGAFVVCWTPGLVVLLLDGLNCRQCGVQHVKRWFLLLALLNSVVNPIIYSYKDEDM
  YGTMKKMICCFSQENPERRPSRIPSTVLSRSDTGSQYIEDSISQGAVCNKSTS
• Function: Receptor for lysophosphatidic acid (LPA), a mediator of diverse cellular activities. May play a role in the development of ovarian cancer. Seems to be coupled to the G(i)/G(o) and G(q) families of heteromeric G proteins.
• Tissue Specificity: Most abundantly expressed in prostate, testes, pancreas, and heart, with moderate levels in lung and ovary. No detectable expression in brain, placenta, liver, skeletal muscle, kidney, spleen, thymus, small intestine, colon, or peripheral blood leukocytes.
• KEGG Pathway:
  Rap1 sig.ling pathway (hsa04015)
  Phospholipase D sig.ling pathway (hsa04072)
  Neuroactive ligand-receptor interaction (hsa04080)
  PI3K-Akt sig.ling pathway (hsa04151)
  Pathways in cancer (hsa05200)
• Reactome Pathway:
  G alpha (i) signalling events (R-HSA-418594)
  Lysosphingolipid and LPA receptors (R-HSA-419408)
  G alpha (q) signalling events (R-HSA-416476)

Molecular Interaction Atlas (MIA) of This DOT

14 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 Lysophosphatidic acid receptor 3 (LPAR3).	[1]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Lysophosphatidic acid receptor 3 (LPAR3).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Lysophosphatidic acid receptor 3 (LPAR3).	[3]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Lysophosphatidic acid receptor 3 (LPAR3).	[5]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Lysophosphatidic acid receptor 3 (LPAR3).	[6]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Lysophosphatidic acid receptor 3 (LPAR3).	[7]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Lysophosphatidic acid receptor 3 (LPAR3).	[8]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Lysophosphatidic acid receptor 3 (LPAR3).	[9]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Lysophosphatidic acid receptor 3 (LPAR3).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Lysophosphatidic acid receptor 3 (LPAR3).	[12]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Lysophosphatidic acid receptor 3 (LPAR3).	[13]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Lysophosphatidic acid receptor 3 (LPAR3).	[14]
Glyphosate	DM0AFY7	Investigative	Glyphosate decreases the expression of Lysophosphatidic acid receptor 3 (LPAR3).	[15]
QUERCITRIN	DM1DH96	Investigative	QUERCITRIN increases the expression of Lysophosphatidic acid receptor 3 (LPAR3).	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Lysophosphatidic acid receptor 3 (LPAR3).	[4]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Lysophosphatidic acid receptor 3 (LPAR3).	[10]

References

• [1] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [2] 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.
• [3] 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.
• [4] 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.
• [5] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [6] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [7] Progesterone regulation of implantation-related genes: new insights into the role of oestrogen. Cell Mol Life Sci. 2007 Apr;64(7-8):1009-32.
• [8] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [9] 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.
• [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] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [12] Epigenetic influences of low-dose bisphenol A in primary human breast epithelial cells. Toxicol Appl Pharmacol. 2010 Oct 15;248(2):111-21.
• [13] 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.
• [14] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [15] Glyphosate-based herbicides at low doses affect canonical pathways in estrogen positive and negative breast cancer cell lines. PLoS One. 2019 Jul 11;14(7):e0219610. doi: 10.1371/journal.pone.0219610. eCollection 2019.
• [16] Molecular mechanisms of quercitrin-induced apoptosis in non-small cell lung cancer. Arch Med Res. 2014 Aug;45(6):445-54.