Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT80FYA3)

• DOT Name: G-protein coupled receptor 161 (GPR161)
• Synonyms: G-protein coupled receptor RE2
• Gene Name: GPR161
• Related Disease:
  Neural tube defect
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Hepatitis C virus infection
  Medulloblastoma
  Neoplasm
  Triple negative breast cancer
  Acute myelogenous leukaemia
  Pituitary stalk interruption syndrome
• UniProt ID: GP161_HUMAN
• PDB ID: 8KH4
• Pfam ID: PF00001
• Sequence:
  MSLNSSLSCRKELSNLTEEEGGEGGVIITQFIAIIVITIFVCLGNLVIVVTLYKKSYLLT
  LSNKFVFSLTLSNFLLSVLVLPFVVTSSIRREWIFGVVWCNFSALLYLLISSASMLTLGV
  IAIDRYYAVLYPMVYPMKITGNRAVMALVYIWLHSLIGCLPPLFGWSSVEFDEFKWMCVA
  AWHREPGYTAFWQIWCALFPFLVMLVCYGFIFRVARVKARKVHCGTVVIVEEDAQRTGRK
  NSSTSTSSSGSRRNAFQGVVYSANQCKALITILVVLGAFMVTWGPYMVVIASEALWGKSS
  VSPSLETWATWLSFASAVCHPLIYGLWNKTVRKELLGMCFGDRYYREPFVQRQRTSRLFS
  ISNRITDLGLSPHLTALMAGGQPLGHSSSTGDTGFSCSQDSGTDMMLLEDYTSDDNPPSH
  CTCPPKRRSSVTFEDEVEQIKEAAKNSILHVKAEVHKSLDSYAASLAKAIEAEAKINLFG
  EEALPGVLVTARTVPGGGFGGRRGSRTLVSQRLQLQSIEEGDVLAAEQR
• Function: Key negative regulator of Shh signaling, which promotes the processing of GLI3 into GLI3R during neural tube development. Recruited by TULP3 and the IFT-A complex to primary cilia and acts as a regulator of the PKA-dependent basal repression machinery in Shh signaling by increasing cAMP levels, leading to promote the PKA-dependent processing of GLI3 into GLI3R and repress the Shh signaling. In presence of SHH, it is removed from primary cilia and is internalized into recycling endosomes, preventing its activity and allowing activation of the Shh signaling. Its ligand is unknown.
• KEGG Pathway: Hedgehog sig.ling pathway (hsa04340)
• Reactome Pathway:
  Hedgehog 'on' state (R-HSA-5632684)
  Hedgehog 'off' state (R-HSA-5610787)

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neural tube defect	DIS5J95E	Definitive	Genetic Variation	[1]
Breast cancer	DIS7DPX1	Strong	Biomarker	[2]
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[3]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[2]
Hepatitis C virus infection	DISQ0M8R	Strong	Biomarker	[4]
Medulloblastoma	DISZD2ZL	Strong	Genetic Variation	[5]
Neoplasm	DISZKGEW	Strong	Genetic Variation	[6]
Triple negative breast cancer	DISAMG6N	Strong	Biomarker	[2]
Acute myelogenous leukaemia	DISCSPTN	moderate	Genetic Variation	[7]
Pituitary stalk interruption syndrome	DISGSN5T	Supportive	Autosomal dominant	[8]

8 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 G-protein coupled receptor 161 (GPR161).	[9]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of G-protein coupled receptor 161 (GPR161).	[10]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of G-protein coupled receptor 161 (GPR161).	[11]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of G-protein coupled receptor 161 (GPR161).	[12]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of G-protein coupled receptor 161 (GPR161).	[13]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of G-protein coupled receptor 161 (GPR161).	[14]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of G-protein coupled receptor 161 (GPR161).	[16]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of G-protein coupled receptor 161 (GPR161).	[18]

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 G-protein coupled receptor 161 (GPR161).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of G-protein coupled receptor 161 (GPR161).	[17]

References

• [1] Dominant negative GPR161 rare variants are risk factors of human spina bifida.Hum Mol Genet. 2019 Jan 15;28(2):200-208. doi: 10.1093/hmg/ddy339.
• [2] G-protein-coupled receptor GPR161 is overexpressed in breast cancer and is a promoter of cell proliferation and invasion.Proc Natl Acad Sci U S A. 2014 Mar 18;111(11):4191-6. doi: 10.1073/pnas.1320239111. Epub 2014 Mar 5.
• [3] Association analysis identifies 65 new breast cancer risk loci.Nature. 2017 Nov 2;551(7678):92-94. doi: 10.1038/nature24284. Epub 2017 Oct 23.
• [4] A method for detecting hepatitis C envelope specific memory B cells from multiple genotypes using cocktail E2 tetramers.J Immunol Methods. 2019 Sep;472:65-74. doi: 10.1016/j.jim.2019.06.016. Epub 2019 Jun 19.
• [5] Germline GPR161 Mutations Predispose to Pediatric Medulloblastoma.J Clin Oncol. 2020 Jan 1;38(1):43-50. doi: 10.1200/JCO.19.00577. Epub 2019 Oct 14.
• [6] Basal Suppression of the Sonic Hedgehog Pathway by the G-Protein-Coupled Receptor Gpr161 Restricts Medulloblastoma Pathogenesis.Cell Rep. 2018 Jan 30;22(5):1169-1184. doi: 10.1016/j.celrep.2018.01.018.
• [7] Genome-wide haplotype association study identify the FGFR2 gene as a risk gene for acute myeloid leukemia.Oncotarget. 2017 Jan 31;8(5):7891-7899. doi: 10.18632/oncotarget.13631.
• [8] Whole-exome sequencing identifies homozygous GPR161 mutation in a family with pituitary stalk interruption syndrome. J Clin Endocrinol Metab. 2015 Jan;100(1):E140-7. doi: 10.1210/jc.2014-1984.
• [9] Stem cell transcriptome responses and corresponding biomarkers that indicate the transition from adaptive responses to cytotoxicity. Chem Res Toxicol. 2017 Apr 17;30(4):905-922.
• [10] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [11] 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.
• [12] Estradiol and selective estrogen receptor modulators differentially regulate target genes with estrogen receptors alpha and beta. Mol Biol Cell. 2004 Mar;15(3):1262-72. doi: 10.1091/mbc.e03-06-0360. Epub 2003 Dec 29.
• [13] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [14] 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.
• [15] 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.
• [16] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [17] 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.
• [18] 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.