Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT3HY17B)

• DOT Name: Glycoprotein hormone alpha-2 (GPHA2)
• Synonyms: Putative secreted protein Zsig51; Thyrostimulin subunit alpha
• Gene Name: GPHA2
• Related Disease:
  Brain neoplasm
  Nasopharyngeal carcinoma
  Glaucoma/ocular hypertension
  Melanoma
• UniProt ID: GPHA2_HUMAN
• Sequence:
  MPMASPQTLVLYLLVLAVTEAWGQEAVIPGCHLHPFNVTVRSDRQGTCQGSHVAQACVGH
  CESSAFPSRYSVLVASGYRHNITSVSQCCTISGLKKVKVQLQCVGSRREELEIFTARACQ
  CDMCRLSRY
• Function: Functions as a heterodimeric glycoprotein hormone with GPHB5 able to bind and activate the thyroid-stimulating hormone receptor (TSHR), leading to increased cAMP production. Plays a central role in controlling thyroid cell metabolism.
• Tissue Specificity: Found in a variety of tissues.
• KEGG Pathway:
  cAMP sig.ling pathway (hsa04024)
  Neuroactive ligand-receptor interaction (hsa04080)
• Reactome Pathway:
  G alpha (s) signalling events (R-HSA-418555)
  Hormone ligand-binding receptors (R-HSA-375281)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Brain neoplasm	DISY3EKS	Strong	Biomarker	[1]
Nasopharyngeal carcinoma	DISAOTQ0	moderate	Altered Expression	[2]
Glaucoma/ocular hypertension	DISLBXBY	Limited	Biomarker	[3]
Melanoma	DIS1RRCY	Limited	Biomarker	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Glycoprotein hormone alpha-2 (GPHA2).	[5]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Glycoprotein hormone alpha-2 (GPHA2).	[6]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Glycoprotein hormone alpha-2 (GPHA2).	[7]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Glycoprotein hormone alpha-2 (GPHA2).	[8]

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 Glycoprotein hormone alpha-2 (GPHA2).	[9]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Glycoprotein hormone alpha-2 (GPHA2).	[10]

References

• [1] Stereotactic radiosurgery (SRS) alone versus whole brain radiotherapy plus SRS in patients with 1 to 4 brain metastases from non-small cell lung cancer stratified by the graded prognostic assessment: A meta-analysis (PRISMA) of randomized control trials.Medicine (Baltimore). 2018 Aug;97(33):e11777. doi: 10.1097/MD.0000000000011777.
• [2] Exercise affects platelet-promoted tumor cell adhesion and invasion to endothelium.Eur J Appl Physiol. 2009 Feb;105(3):393-401. doi: 10.1007/s00421-008-0916-2. Epub 2008 Nov 8.
• [3] Classification and Statistical Trend Analysis in Detecting Glaucomatous Visual Field Progression.J Ophthalmol. 2019 May 28;2019:1583260. doi: 10.1155/2019/1583260. eCollection 2019.
• [4] Aggressiveness of human melanoma xenograft models is promoted by aneuploidy-driven gene expression deregulation.Oncotarget. 2012 Apr;3(4):399-413. doi: 10.18632/oncotarget.473.
• [5] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [6] 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.
• [7] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [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] 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.
• [10] 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.