Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT1NXSMN)

• DOT Name: Ovarian cancer G-protein coupled receptor 1 (GPR68)
• Synonyms: OGR-1; G-protein coupled receptor 68; GPR12A; Sphingosylphosphorylcholine receptor
• Gene Name: GPR68
• Related Disease:
  Matthew-Wood syndrome
  Acute myelogenous leukaemia
  Adenocarcinoma
  Amelogenesis imperfecta
  Amelogenesis imperfecta, hypomaturation type, IIa6
  Bone osteosarcoma
  Childhood myelodysplastic syndrome
  Colonic neoplasm
  Colorectal carcinoma
  Cowden disease
  Crohn disease
  Endometrial cancer
  Endometrial carcinoma
  Inflammatory bowel disease
  Medulloblastoma
  Metastatic malignant neoplasm
  Myelodysplastic syndrome
  Neoplasm
  Neuroendocrine neoplasm
  Osteosarcoma
  Pancreatic cancer
  Paraganglioma
  Pheochromocytoma
  Prostate cancer
  Prostate carcinoma
  Thyroid gland carcinoma
  Amelogenesis imperfecta type 2
  Advanced cancer
• UniProt ID: OGR1_HUMAN
• Pfam ID: PF00001
• Sequence:
  MGNITADNSSMSCTIDHTIHQTLAPVVYVTVLVVGFPANCLSLYFGYLQIKARNELGVYL
  CNLTVADLFYICSLPFWLQYVLQHDNWSHGDLSCQVCGILLYENIYISVGFLCCISVDRY
  LAVAHPFRFHQFRTLKAAVGVSVVIWAKELLTSIYFLMHEEVIEDENQHRVCFEHYPIQA
  WQRAINYYRFLVGFLFPICLLLASYQGILRAVRRSHGTQKSRKDQIQRLVLSTVVIFLAC
  FLPYHVLLLVRSVWEASCDFAKGVFNAYHFSLLLTSFNCVADPVLYCFVSETTHRDLARL
  RGACLAFLTCSRTGRAREAYPLGAPEASGKSGAQGEEPELLTKLHPAFQTPNSPGSGGFP
  TGRLA
• Function: Proton-sensing receptor involved in pH homeostasis. May represents an osteoblastic pH sensor regulating cell-mediated responses to acidosis in bone. Mediates its action by association with G proteins that stimulates inositol phosphate (IP) production or Ca(2+) mobilization. The receptor is almost silent at pH 7.8 but fully activated at pH 6.8. Also functions as a metastasis suppressor gene in prostate cancer.
• Tissue Specificity: Found at low level in a wide range of tissues, but significantly expressed in lung, kidney, bone and nervous system.
• Reactome Pathway:
  G alpha (q) signalling events (R-HSA-416476)
  Class A/1 (Rhodopsin-like receptors) (R-HSA-373076)

Molecular Interaction Atlas (MIA) of This DOT

28 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Matthew-Wood syndrome	DISA7HR7	Definitive	Biomarker	[1]
Acute myelogenous leukaemia	DISCSPTN	Strong	Altered Expression	[2]
Adenocarcinoma	DIS3IHTY	Strong	Altered Expression	[3]
Amelogenesis imperfecta	DISGYR9E	Strong	Genetic Variation	[4]
Amelogenesis imperfecta, hypomaturation type, IIa6	DISWS0HI	Strong	Autosomal recessive	[5]
Bone osteosarcoma	DIST1004	Strong	Altered Expression	[5]
Childhood myelodysplastic syndrome	DISMN80I	Strong	Altered Expression	[6]
Colonic neoplasm	DISSZ04P	Strong	Biomarker	[7]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[7]
Cowden disease	DISMYKCE	Strong	Altered Expression	[8]
Crohn disease	DIS2C5Q8	Strong	Biomarker	[8]
Endometrial cancer	DISW0LMR	Strong	Altered Expression	[3]
Endometrial carcinoma	DISXR5CY	Strong	Altered Expression	[3]
Inflammatory bowel disease	DISGN23E	Strong	Altered Expression	[8]
Medulloblastoma	DISZD2ZL	Strong	Altered Expression	[9]
Metastatic malignant neoplasm	DIS86UK6	Strong	Biomarker	[10]
Myelodysplastic syndrome	DISYHNUI	Strong	Altered Expression	[6]
Neoplasm	DISZKGEW	Strong	Biomarker	[6]
Neuroendocrine neoplasm	DISNPLOO	Strong	Altered Expression	[3]
Osteosarcoma	DISLQ7E2	Strong	Altered Expression	[5]
Pancreatic cancer	DISJC981	Strong	Altered Expression	[6]
Paraganglioma	DIS2XXH5	Strong	Altered Expression	[3]
Pheochromocytoma	DIS56IFV	Strong	Altered Expression	[3]
Prostate cancer	DISF190Y	Strong	Biomarker	[10]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[10]
Thyroid gland carcinoma	DISMNGZ0	Strong	Altered Expression	[3]
Amelogenesis imperfecta type 2	DISX8NN4	Supportive	Autosomal recessive	[4]
Advanced cancer	DISAT1Z9	Limited	Altered Expression	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Ovarian cancer G-protein coupled receptor 1 (GPR68).	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Ovarian cancer G-protein coupled receptor 1 (GPR68).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Ovarian cancer G-protein coupled receptor 1 (GPR68).	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Ovarian cancer G-protein coupled receptor 1 (GPR68).	[12]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Ovarian cancer G-protein coupled receptor 1 (GPR68).	[13]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Ovarian cancer G-protein coupled receptor 1 (GPR68).	[14]
Dexamethasone	DMMWZET	Approved	Dexamethasone decreases the expression of Ovarian cancer G-protein coupled receptor 1 (GPR68).	[15]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Ovarian cancer G-protein coupled receptor 1 (GPR68).	[17]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Ovarian cancer G-protein coupled receptor 1 (GPR68).	[19]

References

• [1] GPR68, a proton-sensing GPCR, mediates interaction of cancer-associated fibroblasts and cancer cells.FASEB J. 2018 Mar;32(3):1170-1183. doi: 10.1096/fj.201700834R. Epub 2018 Jan 3.
• [2] A calcium- and calpain-dependent pathway determines the response to lenalidomide in myelodysplastic syndromes.Nat Med. 2016 Jul;22(7):727-34. doi: 10.1038/nm.4127. Epub 2016 Jun 13.
• [3] Comprehensive Assessment of GPR68 Expression in Normal and Neoplastic Human Tissues Using a Novel Rabbit Monoclonal Antibody.Int J Mol Sci. 2019 Oct 23;20(21):5261. doi: 10.3390/ijms20215261.
• [4] Mutations in the pH-Sensing G-protein-Coupled Receptor GPR68 Cause Amelogenesis Imperfecta. Am J Hum Genet. 2016 Oct 6;99(4):984-990. doi: 10.1016/j.ajhg.2016.08.020. Epub 2016 Sep 29.
• [5] Proton-sensing G-protein-coupled receptors. Nature. 2003 Sep 4;425(6953):93-8. doi: 10.1038/nature01905.
• [6] GPR68: An Emerging Drug Target in Cancer.Int J Mol Sci. 2019 Jan 28;20(3):559. doi: 10.3390/ijms20030559.
• [7] Functional profiling of microtumors to identify cancer associated fibroblast-derived drug targets.Oncotarget. 2017 Oct 20;8(59):99913-99930. doi: 10.18632/oncotarget.21915. eCollection 2017 Nov 21.
• [8] Intestinal Activation of pH-Sensing Receptor OGR1 [GPR68] Contributes to Fibrogenesis.J Crohns Colitis. 2018 Nov 15;12(11):1348-1358. doi: 10.1093/ecco-jcc/jjy118.
• [9] Functional expression of calcium-permeable canonical transient receptor potential 4-containing channels promotes migration of medulloblastoma cells.J Physiol. 2017 Aug 15;595(16):5525-5544. doi: 10.1113/JP274659. Epub 2017 Jul 20.
• [10] Ovarian cancer G protein-coupled receptor 1, a new metastasis suppressor gene in prostate cancer.J Natl Cancer Inst. 2007 Sep 5;99(17):1313-27. doi: 10.1093/jnci/djm107. Epub 2007 Aug 28.
• [11] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [12] 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.
• [13] 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.
• [14] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [15] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [16] 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.
• [17] 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.
• [18] 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.
• [19] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.