Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTMVHF9E)

• DOT Name: Leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5)
• Synonyms: G-protein coupled receptor 49; G-protein coupled receptor 67; G-protein coupled receptor HG38
• Gene Name: LGR5
• UniProt ID: LGR5_HUMAN
• PDB ID: 4BSR; 4BSS; 4BST; 4BSU; 4KNG; 4UFR; 4UFS
• Pfam ID: PF00001 ; PF00560 ; PF13855 ; PF01462
• Sequence:
  MDTSRLGVLLSLPVLLQLATGGSSPRSGVLLRGCPTHCHCEPDGRMLLRVDCSDLGLSEL
  PSNLSVFTSYLDLSMNNISQLLPNPLPSLRFLEELRLAGNALTYIPKGAFTGLYSLKVLM
  LQNNQLRHVPTEALQNLRSLQSLRLDANHISYVPPSCFSGLHSLRHLWLDDNALTEIPVQ
  AFRSLSALQAMTLALNKIHHIPDYAFGNLSSLVVLHLHNNRIHSLGKKCFDGLHSLETLD
  LNYNNLDEFPTAIRTLSNLKELGFHSNNIRSIPEKAFVGNPSLITIHFYDNPIQFVGRSA
  FQHLPELRTLTLNGASQITEFPDLTGTANLESLTLTGAQISSLPQTVCNQLPNLQVLDLS
  YNLLEDLPSFSVCQKLQKIDLRHNEIYEIKVDTFQQLLSLRSLNLAWNKIAIIHPNAFST
  LPSLIKLDLSSNLLSSFPITGLHGLTHLKLTGNHALQSLISSENFPELKVIEMPYAYQCC
  AFGVCENAYKISNQWNKGDNSSMDDLHKKDAGMFQAQDERDLEDFLLDFEEDLKALHSVQ
  CSPSPGPFKPCEHLLDGWLIRIGVWTIAVLALTCNALVTSTVFRSPLYISPIKLLIGVIA
  AVNMLTGVSSAVLAGVDAFTFGSFARHGAWWENGVGCHVIGFLSIFASESSVFLLTLAAL
  ERGFSVKYSAKFETKAPFSSLKVIILLCALLALTMAAVPLLGGSKYGASPLCLPLPFGEP
  STMGYMVALILLNSLCFLMMTIAYTKLYCNLDKGDLENIWDCSMVKHIALLLFTNCILNC
  PVAFLSFSSLINLTFISPEVIKFILLVVVPLPACLNPLLYILFNPHFKEDLVSLRKQTYV
  WTRSKHPSLMSINSDDVEKQSCDSTQALVTFTSSSITYDLPPSSVPSPAYPVTESCHLSS
  VAFVPCL
• Function: Receptor for R-spondins that potentiates the canonical Wnt signaling pathway and acts as a stem cell marker of the intestinal epithelium and the hair follicle. Upon binding to R-spondins (RSPO1, RSPO2, RSPO3 or RSPO4), associates with phosphorylated LRP6 and frizzled receptors that are activated by extracellular Wnt receptors, triggering the canonical Wnt signaling pathway to increase expression of target genes. In contrast to classical G-protein coupled receptors, does not activate heterotrimeric G-proteins to transduce the signal. Involved in the development and/or maintenance of the adult intestinal stem cells during postembryonic development.
• Tissue Specificity: Expressed in skeletal muscle, placenta, spinal cord, and various region of brain. Expressed at the base of crypts in colonic and small mucosa stem cells. In premalignant cancer expression is not restricted to the cript base. Overexpressed in cancers of the ovary, colon and liver.
• KEGG Pathway: Wnt sig.ling pathway (hsa04310)
• Reactome Pathway: Regulation of FZD by ubiquitination (R-HSA-4641263)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5).	[2]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5).	[3]
Arsenic	DMTL2Y1	Approved	Arsenic affects the expression of Leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5).	[4]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5).	[5]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5).	[6]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5).	[7]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5).	[8]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5).	[9]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5).	[10]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5).	[7]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil decreases the expression of Leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5).	[11]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5).	[12]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5).	[8]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of Leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5).	[13]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5).	[15]
CHIR-99021	DMB8MNU	Patented	CHIR-99021 increases the expression of Leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5).	[17]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5).	[18]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5).	[19]
Okadaic acid	DM47CO1	Investigative	Okadaic acid increases the expression of Leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5).	[20]
6-bromoindirubin-3-oxime	DM12WYV	Investigative	6-bromoindirubin-3-oxime increases the expression of Leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5).	[17]

2 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 G-protein coupled receptor 5 (LGR5).	[14]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5).	[16]

References

• [1] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [2] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [3] Bisphenol A effects on gene expression in adipocytes from children: association with metabolic disorders. J Mol Endocrinol. 2015 Jun;54(3):289-303.
• [4] The aquaglyceroporin AQP9 contributes to the sex-specific effects of in utero arsenic exposure on placental gene expression. Environ Health. 2017 Jun 14;16(1):59. doi: 10.1186/s12940-017-0267-8.
• [5] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [6] Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
• [7] Time series analysis of oxidative stress response patterns in HepG2: a toxicogenomics approach. Toxicology. 2013 Apr 5;306:24-34.
• [8] 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.
• [9] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [10] The contribution of methotrexate exposure and host factors on transcriptional variance in human liver. Toxicol Sci. 2007 Jun;97(2):582-94.
• [11] Evaluation of developmental toxicity using undifferentiated human embryonic stem cells. J Appl Toxicol. 2015 Feb;35(2):205-18.
• [12] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [13] Fluorinated N,N-dialkylaminostilbenes for Wnt pathway inhibition and colon cancer repression. J Med Chem. 2011 Mar 10;54(5):1288-97. doi: 10.1021/jm101248v. Epub 2011 Feb 3.
• [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.
• [15] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [16] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [17] Analysis of glycogen synthase kinase inhibitors that regulate cytochrome P450 expression in primary human hepatocytes by activation of beta-catenin, aryl hydrocarbon receptor and pregnane X receptor signaling. Toxicol Sci. 2015 Nov;148(1):261-75.
• [18] Bisphenol A Analogues Suppress Spheroid Attachment on Human Endometrial Epithelial Cells through Modulation of Steroid Hormone Receptors Signaling Pathway. Cells. 2021 Oct 26;10(11):2882. doi: 10.3390/cells10112882.
• [19] 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.
• [20] Okadaic acid activates Wnt/-catenin-signaling in human HepaRG cells. Arch Toxicol. 2019 Jul;93(7):1927-1939. doi: 10.1007/s00204-019-02489-4. Epub 2019 May 21.