Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTRJGZP8)

• DOT Name: Alpha-1-acid glycoprotein 2 (ORM2)
• Synonyms: AGP 2; Orosomucoid-2; OMD 2
• Gene Name: ORM2
• Related Disease:
  Alzheimer disease
  Behcet disease
  Brain disease
  Cholangiocarcinoma
  Cholangitis
  Congenital contractural arachnodactyly
  Coronary heart disease
  Crohn disease
  Encephalitis
  Metastatic malignant neoplasm
  Neoplasm
  Primary sclerosing cholangitis
  Trigeminal neuralgia
  Ulcerative colitis
  Hepatocellular carcinoma
  Colorectal carcinoma
• UniProt ID: A1AG2_HUMAN
• PDB ID: 3APU; 3APV; 3APW; 3APX; 7OUB
• Pfam ID: PF00061
• Sequence:
  MALSWVLTVLSLLPLLEAQIPLCANLVPVPITNATLDRITGKWFYIASAFRNEEYNKSVQ
  EIQATFFYFTPNKTEDTIFLREYQTRQNQCFYNSSYLNVQRENGTVSRYEGGREHVAHLL
  FLRDTKTLMFGSYLDDEKNWGLSFYADKPETTKEQLGEFYEALDCLCIPRSDVMYTDWKK
  DKCEPLEKQHEKERKQEEGES
• Function: Functions as a transport protein in the blood stream. Binds various hydrophobic ligands in the interior of its beta-barrel domain. Also binds synthetic drugs and influences their distribution and availability. Appears to function in modulating the activity of the immune system during the acute-phase reaction.
• Tissue Specificity: Expressed by the liver and secreted in plasma.
• Reactome Pathway:
  Neutrophil degranulation (R-HSA-6798695)
  Platelet degranulation (R-HSA-114608)

Molecular Interaction Atlas (MIA) of This DOT

16 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Alzheimer disease	DISF8S70	Strong	Biomarker	[1]
Behcet disease	DISSYMBS	Strong	Genetic Variation	[2]
Brain disease	DIS6ZC3X	Strong	Biomarker	[1]
Cholangiocarcinoma	DIS71F6X	Strong	Biomarker	[3]
Cholangitis	DIS9U3YN	Strong	Altered Expression	[3]
Congenital contractural arachnodactyly	DISOM1K7	Strong	Biomarker	[3]
Coronary heart disease	DIS5OIP1	Strong	Biomarker	[4]
Crohn disease	DIS2C5Q8	Strong	Biomarker	[2]
Encephalitis	DISLD1RL	Strong	Biomarker	[1]
Metastatic malignant neoplasm	DIS86UK6	Strong	Biomarker	[5]
Neoplasm	DISZKGEW	Strong	Biomarker	[5]
Primary sclerosing cholangitis	DISTH5WJ	Strong	Biomarker	[6]
Trigeminal neuralgia	DIS31ZY6	Strong	Biomarker	[7]
Ulcerative colitis	DIS8K27O	Strong	Altered Expression	[2]
Hepatocellular carcinoma	DIS0J828	moderate	Biomarker	[8]
Colorectal carcinoma	DIS5PYL0	Limited	Biomarker	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Alpha-1-acid glycoprotein 2 (ORM2).	[10]

14 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 Alpha-1-acid glycoprotein 2 (ORM2).	[11]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Alpha-1-acid glycoprotein 2 (ORM2).	[12]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Alpha-1-acid glycoprotein 2 (ORM2).	[13]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Alpha-1-acid glycoprotein 2 (ORM2).	[14]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Alpha-1-acid glycoprotein 2 (ORM2).	[15]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Alpha-1-acid glycoprotein 2 (ORM2).	[15]
Panobinostat	DM58WKG	Approved	Panobinostat decreases the expression of Alpha-1-acid glycoprotein 2 (ORM2).	[16]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Alpha-1-acid glycoprotein 2 (ORM2).	[17]
Ursodeoxycholic acid	DMCUT21	Approved	Ursodeoxycholic acid affects the expression of Alpha-1-acid glycoprotein 2 (ORM2).	[18]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Alpha-1-acid glycoprotein 2 (ORM2).	[16]
Belinostat	DM6OC53	Phase 2	Belinostat decreases the expression of Alpha-1-acid glycoprotein 2 (ORM2).	[16]
ACYLINE	DM9GRTK	Phase 2	ACYLINE decreases the expression of Alpha-1-acid glycoprotein 2 (ORM2).	[20]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Alpha-1-acid glycoprotein 2 (ORM2).	[21]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Alpha-1-acid glycoprotein 2 (ORM2).	[22]

5 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Imipramine	DM2NUH3	Approved	Imipramine affects the binding of Alpha-1-acid glycoprotein 2 (ORM2).	[19]
Lidocaine	DML4ZOT	Approved	Lidocaine affects the binding of Alpha-1-acid glycoprotein 2 (ORM2).	[19]
Methadone	DMTW6IU	Approved	Methadone affects the binding of Alpha-1-acid glycoprotein 2 (ORM2).	[19]
Disopyramide	DM5SYZP	Approved	Disopyramide affects the binding of Alpha-1-acid glycoprotein 2 (ORM2).	[19]
Chlorpromazine	DMBGZI3	Phase 3 Trial	Chlorpromazine affects the binding of Alpha-1-acid glycoprotein 2 (ORM2).	[19]

References

• [1] Astrocytic Orosomucoid-2 Modulates Microglial Activation and Neuroinflammation.J Neurosci. 2017 Mar 15;37(11):2878-2894. doi: 10.1523/JNEUROSCI.2534-16.2017. Epub 2017 Feb 13.
• [2] Antibodies against glycoprotein 2 display diagnostic advantages over ASCA in distinguishing CD from intestinal tuberculosis and intestinal Behet's disease.Clin Transl Gastroenterol. 2018 Feb 15;9(2):e133. doi: 10.1038/ctg.2018.1.
• [3] Plasma orosomucoid 2 as a potential risk marker of cholangiocarcinoma.Cancer Biomark. 2017;18(1):27-34. doi: 10.3233/CBM-160670.
• [4] Myocardial Injury Is Distinguished from Stable Angina by a Set of Candidate Plasma Biomarkers Identified Using iTRAQ/MRM-Based Approach.J Proteome Res. 2018 Jan 5;17(1):499-515. doi: 10.1021/acs.jproteome.7b00651. Epub 2017 Nov 7.
• [5] Orosomucoid 2 inhibits tumor metastasis and is upregulated by CCAAT/enhancer binding protein in hepatocellular carcinomas.Oncotarget. 2015 Jun 30;6(18):16106-19. doi: 10.18632/oncotarget.3867.
• [6] Mucosal Autoimmunity to Cell-Bound GP2 Isoforms Is a Sensitive Marker in PSC and Associated With the Clinical Phenotype.Front Immunol. 2018 Aug 28;9:1959. doi: 10.3389/fimmu.2018.01959. eCollection 2018.
• [7] Different Pain States of Trigeminal Neuralgia Make Significant Changes in the Plasma Proteome and Some Biochemical Parameters: a Preliminary Cohort Study.J Mol Neurosci. 2018 Dec;66(4):524-534. doi: 10.1007/s12031-018-1183-2. Epub 2018 Oct 17.
• [8] Straightforward and Highly Efficient Strategy for Hepatocellular Carcinoma Glycoprotein Biomarker Discovery Using a Nonglycopeptide-Based Mass Spectrometry Pipeline.Anal Chem. 2019 Oct 1;91(19):12435-12443. doi: 10.1021/acs.analchem.9b03074. Epub 2019 Sep 9.
• [9] Expression of angiostatic factors in colorectal cancer.Int J Oncol. 1999 Dec;15(6):1221-5. doi: 10.3892/ijo.15.6.1221.
• [10] 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.
• [11] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [12] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [13] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [14] 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.
• [15] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [16] 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.
• [17] 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.
• [18] Gene expression profiling of early primary biliary cirrhosis: possible insights into the mechanism of action of ursodeoxycholic acid. Liver Int. 2008 Aug;28(7):997-1010. doi: 10.1111/j.1478-3231.2008.01744.x. Epub 2008 Apr 15.
• [19] Binding of disopyramide, methadone, dipyridamole, chlorpromazine, lignocaine and progesterone to the two main genetic variants of human alpha 1-acid glycoprotein: evidence for drug-binding differences between the variants and for the presence of two separate drug-binding sites on alpha 1-acid glycoprotein. Pharmacogenetics. 1996 Oct;6(5):403-15. doi: 10.1097/00008571-199610000-00004.
• [20] Intraprostatic androgens and androgen-regulated gene expression persist after testosterone suppression: therapeutic implications for castration-resistant prostate cancer. Cancer Res. 2007 May 15;67(10):5033-41.
• [21] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [22] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.