Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTRILX7G)

• DOT Name: G-protein coupled receptor 183 (GPR183)
• Synonyms: Epstein-Barr virus-induced G-protein coupled receptor 2; EBI2; EBV-induced G-protein coupled receptor 2; hEBI2
• Gene Name: GPR183
• UniProt ID: GP183_HUMAN
• PDB ID: 7TUY; 7TUZ
• Pfam ID: PF00001
• Sequence:
  MDIQMANNFTPPSATPQGNDCDLYAHHSTARIVMPLHYSLVFIIGLVGNLLALVVIVQNR
  KKINSTTLYSTNLVISDILFTTALPTRIAYYAMGFDWRIGDALCRITALVFYINTYAGVN
  FMTCLSIDRFIAVVHPLRYNKIKRIEHAKGVCIFVWILVFAQTLPLLINPMSKQEAERIT
  CMEYPNFEETKSLPWILLGACFIGYVLPLIIILICYSQICCKLFRTAKQNPLTEKSGVNK
  KALNTIILIIVVFVLCFTPYHVAIIQHMIKKLRFSNFLECSQRHSFQISLHFTVCLMNFN
  CCMDPFIYFFACKGYKRKVMRMLKRQVSVSISSAVKSAPEENSREMTETQMMIHSKSSNG
  K
• Function: G-protein coupled receptor expressed in lymphocytes that acts as a chemotactic receptor for B-cells, T-cells, splenic dendritic cells, monocytes/macrophages and astrocytes. Receptor for oxysterol 7-alpha,25-dihydroxycholesterol (7-alpha,25-OHC) and other related oxysterols. Mediates cell positioning and movement of a number of cells by binding the 7-alpha,25-OHC ligand that forms a chemotactic gradient. Binding of 7-alpha,25-OHC mediates the correct localization of B-cells during humoral immune responses. Guides B-cell movement along the B-cell zone-T-cell zone boundary and later to interfollicular and outer follicular regions. Its specific expression during B-cell maturation helps position B-cells appropriately for mounting T-dependent antibody responses. Collaborates with CXCR5 to mediate B-cell migration; probably by forming a heterodimer with CXCR5 that affects the interaction between of CXCL13 and CXCR5. Also acts as a chemotactic receptor for some T-cells upon binding to 7-alpha,25-OHC ligand. Promotes follicular helper T (Tfh) cells differentiation by positioning activated T-cells at the follicle-T-zone interface, promoting contact of newly activated CD4 T-cells with activated dendritic cells and exposing them to Tfh-cell-promoting inducible costimulator (ICOS) ligand. Expression in splenic dendritic cells is required for their homeostasis, localization and ability to induce B- and T-cell responses: GPR183 acts as a chemotactic receptor in dendritic cells that mediates the accumulation of CD4(+) dendritic cells in bridging channels. Regulates migration of astrocytes and is involved in communication between astrocytes and macrophages. Promotes osteoclast precursor migration to bone surfaces. Signals constitutively through G(i)-alpha, but not G(s)-alpha or G(q)-alpha. Signals constitutively also via MAPK1/3 (ERK1/2).
• Tissue Specificity: Expressed abundantly in lymphoid tissues such as spleen and lymph node, and in B- and T-lymphocytes . Also highly expressed in lung, heart and gastrointestinal tract, and weakly expressed in the urogenital system and brain . Expressed in astrocytes .
• Reactome Pathway:
  G alpha (i) signalling events (R-HSA-418594)
  Class A/1 (Rhodopsin-like receptors) (R-HSA-373076)

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 G-protein coupled receptor 183 (GPR183).	[1]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of G-protein coupled receptor 183 (GPR183).	[2]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of G-protein coupled receptor 183 (GPR183).	[3]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of G-protein coupled receptor 183 (GPR183).	[4]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of G-protein coupled receptor 183 (GPR183).	[5]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of G-protein coupled receptor 183 (GPR183).	[1]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of G-protein coupled receptor 183 (GPR183).	[6]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of G-protein coupled receptor 183 (GPR183).	[7]
Panobinostat	DM58WKG	Approved	Panobinostat decreases the expression of G-protein coupled receptor 183 (GPR183).	[1]
Irinotecan	DMP6SC2	Approved	Irinotecan increases the expression of G-protein coupled receptor 183 (GPR183).	[8]
Pioglitazone	DMKJ485	Approved	Pioglitazone decreases the expression of G-protein coupled receptor 183 (GPR183).	[9]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of G-protein coupled receptor 183 (GPR183).	[1]
MGCD-0103	DM726HX	Phase 2	MGCD-0103 decreases the expression of G-protein coupled receptor 183 (GPR183).	[1]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of G-protein coupled receptor 183 (GPR183).	[11]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of G-protein coupled receptor 183 (GPR183).	[12]
Tacedinaline	DM1Z74X	Discontinued in Phase 2	Tacedinaline decreases the expression of G-protein coupled receptor 183 (GPR183).	[1]
Scriptaid	DM9JZ21	Preclinical	Scriptaid decreases the expression of G-protein coupled receptor 183 (GPR183).	[1]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of G-protein coupled receptor 183 (GPR183).	[1]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of G-protein coupled receptor 183 (GPR183).	[14]
Butanoic acid	DMTAJP7	Investigative	Butanoic acid decreases the expression of G-protein coupled receptor 183 (GPR183).	[1]
Octanedioic acid bis-hydroxyamide	DMJNQ9K	Investigative	Octanedioic acid bis-hydroxyamide decreases the expression of G-protein coupled receptor 183 (GPR183).	[1]

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 decreases the methylation of G-protein coupled receptor 183 (GPR183).	[10]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the methylation of G-protein coupled receptor 183 (GPR183).	[13]

References

• [1] Development and validation of the TGx-HDACi transcriptomic biomarker to detect histone deacetylase inhibitors in human TK6 cells. Arch Toxicol. 2021 May;95(5):1631-1645. doi: 10.1007/s00204-021-03014-2. Epub 2021 Mar 26.
• [2] 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.
• [3] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [4] 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.
• [5] Arsenic suppresses gene expression in promyelocytic leukemia cells partly through Sp1 oxidation. Blood. 2005 Jul 1;106(1):304-10.
• [6] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [7] The contribution of methotrexate exposure and host factors on transcriptional variance in human liver. Toxicol Sci. 2007 Jun;97(2):582-94.
• [8] In vitro and in vivo irinotecan-induced changes in expression profiles of cell cycle and apoptosis-associated genes in acute myeloid leukemia cells. Mol Cancer Ther. 2005 Jun;4(6):885-900.
• [9] Peroxisome proliferator activated receptor gamma (PPAR-gama) ligand pioglitazone regulated gene networks in term human primary trophoblast cells. Reprod Toxicol. 2018 Oct;81:99-107.
• [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] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [12] 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.
• [13] 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.
• [14] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.