Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTY3OG71)

• DOT Name: Prorelaxin H2 (RLN2)
• Gene Name: RLN2
• Related Disease:
  Prostate cancer
  Advanced cancer
  Arteriosclerosis
  Atherosclerosis
  Atrial fibrillation
  Cardiomyopathy
  Cardiovascular disease
  Classic Hodgkin lymphoma
  Coronary atherosclerosis
  Early-onset posterior polar cataract
  Endometrial carcinoma
  Fatty liver disease
  High blood pressure
  Huntington disease
  Hyperplasia
  Myocardial infarction
  Myocardial ischemia
  Neoplasm
  Non-alcoholic fatty liver disease
  Pancreatic tumour
  Primary sclerosing cholangitis
  Prostate carcinoma
  Prostate neoplasm
  Renal fibrosis
  Systemic lupus erythematosus
  Thyroid cancer
  Thyroid gland carcinoma
  Ventricular tachycardia
  Bone osteosarcoma
  Osteosarcoma
  Thyroid tumor
  Cardiac failure
  Congestive heart failure
  Glaucoma/ocular hypertension
• UniProt ID: REL2_HUMAN
• PDB ID: 2MV1; 6RLX
• Pfam ID: PF00049
• Sequence:
  MPRLFFFHLLGVCLLLNQFSRAVADSWMEEVIKLCGRELVRAQIAICGMSTWSKRSLSQE
  DAPQTPRPVAEIVPSFINKDTETINMMSEFVANLPQELKLTLSEMQPALPQLQQHVPVLK
  DSSLLFEEFKKLIRNRQSEAADSSPSELKYLGLDTHSRKKRQLYSALANKCCHVGCTKRS
  LARFC
• Function: Relaxin is an ovarian hormone that acts with estrogen to produce dilatation of the birth canal in many mammals. May be involved in remodeling of connective tissues during pregnancy, promoting growth of pubic ligaments and ripening of the cervix.
• Tissue Specificity: Isoform 1 is expressed in the ovary during pregnancy. Also expressed in placenta, decidua and prostate. Isoform 2 is relatively abundant in placenta. It is in much lower abundance in the prostate gland. Not detected in the ovary.
• KEGG Pathway:
  Neuroactive ligand-receptor interaction (hsa04080)
  Relaxin sig.ling pathway (hsa04926)
• Reactome Pathway:
  Relaxin receptors (R-HSA-444821)
  G alpha (s) signalling events (R-HSA-418555)

Molecular Interaction Atlas (MIA) of This DOT

34 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Prostate cancer	DISF190Y	Definitive	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Genetic Variation	[1]
Arteriosclerosis	DISK5QGC	Strong	Biomarker	[2]
Atherosclerosis	DISMN9J3	Strong	Biomarker	[2]
Atrial fibrillation	DIS15W6U	Strong	Biomarker	[3]
Cardiomyopathy	DISUPZRG	Strong	Altered Expression	[4]
Cardiovascular disease	DIS2IQDX	Strong	Biomarker	[5]
Classic Hodgkin lymphoma	DISV1LU6	Strong	Biomarker	[4]
Coronary atherosclerosis	DISKNDYU	Strong	Biomarker	[6]
Early-onset posterior polar cataract	DISJFK9W	Strong	Biomarker	[7]
Endometrial carcinoma	DISXR5CY	Strong	Altered Expression	[8]
Fatty liver disease	DIS485QZ	Strong	Biomarker	[9]
High blood pressure	DISY2OHH	Strong	Biomarker	[10]
Huntington disease	DISQPLA4	Strong	Biomarker	[4]
Hyperplasia	DISK4DFB	Strong	Biomarker	[11]
Myocardial infarction	DIS655KI	Strong	Biomarker	[6]
Myocardial ischemia	DISFTVXF	Strong	Biomarker	[6]
Neoplasm	DISZKGEW	Strong	Biomarker	[7]
Non-alcoholic fatty liver disease	DISDG1NL	Strong	Biomarker	[9]
Pancreatic tumour	DIS3U0LK	Strong	Biomarker	[7]
Primary sclerosing cholangitis	DISTH5WJ	Strong	Biomarker	[7]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[1]
Prostate neoplasm	DISHDKGQ	Strong	Altered Expression	[1]
Renal fibrosis	DISMHI3I	Strong	Biomarker	[12]
Systemic lupus erythematosus	DISI1SZ7	Strong	Biomarker	[10]
Thyroid cancer	DIS3VLDH	Strong	Biomarker	[13]
Thyroid gland carcinoma	DISMNGZ0	Strong	Altered Expression	[13]
Ventricular tachycardia	DISIBXJ3	Strong	Biomarker	[6]
Bone osteosarcoma	DIST1004	moderate	Biomarker	[14]
Osteosarcoma	DISLQ7E2	moderate	Biomarker	[14]
Thyroid tumor	DISLVKMD	Disputed	Biomarker	[13]
Cardiac failure	DISDC067	Limited	Biomarker	[5]
Congestive heart failure	DIS32MEA	Limited	Biomarker	[5]
Glaucoma/ocular hypertension	DISLBXBY	Limited	Biomarker	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Prorelaxin H2 (RLN2).	[16]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Prorelaxin H2 (RLN2).	[17]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Prorelaxin H2 (RLN2).	[18]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Prorelaxin H2 (RLN2).	[19]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Prorelaxin H2 (RLN2).	[20]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Prorelaxin H2 (RLN2).	[16]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Prorelaxin H2 (RLN2).	[20]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Prorelaxin H2 (RLN2).	[21]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Prorelaxin H2 (RLN2).	[16]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Prorelaxin H2 (RLN2).	[23]

1 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 Prorelaxin H2 (RLN2).	[22]

References

• [1] Interaction between angiotensin II and relaxin 2 in the progress of growth and spread of prostate cancer cells.Int J Oncol. 2016 Jun;48(6):2619-28. doi: 10.3892/ijo.2016.3458. Epub 2016 Mar 24.
• [2] Associations between serum relaxin 2, aneurysm formation/size and severity of atherosclerosis: a preliminary prospective analysis.Acta Pharmacol Sin. 2018 Jul;39(7):1243-1248. doi: 10.1038/aps.2018.8. Epub 2018 Mar 22.
• [3] Relaxin reduces susceptibility to post-infarct atrial fibrillation in mice due to anti-fibrotic and anti-inflammatory properties.Biochem Biophys Res Commun. 2017 Aug 26;490(3):643-649. doi: 10.1016/j.bbrc.2017.06.091. Epub 2017 Jun 17.
• [4] Serelaxin treatment promotes adaptive hypertrophy but does not prevent heart failure in experimental peripartum cardiomyopathy.Cardiovasc Res. 2017 May 1;113(6):598-608. doi: 10.1093/cvr/cvw245.
• [5] Serelaxin (recombinant human relaxin-2) treatment affects the endogenous synthesis of long chain poly-unsaturated fatty acids and induces substantial alterations of lipidome and metabolome profiles in rat cardiac tissue.Pharmacol Res. 2019 Jun;144:51-65. doi: 10.1016/j.phrs.2019.04.009. Epub 2019 Apr 5.
• [6] Chronic lower-dose relaxin administration protects from arrhythmia in experimental myocardial infarction due to anti-inflammatory and anti-fibrotic properties.Int J Cardiol. 2018 Jan 1;250:21-28. doi: 10.1016/j.ijcard.2017.09.017.
• [7] Nano-targeted relaxin impairs fibrosis and tumor growth in pancreatic cancer and improves the efficacy of gemcitabine in vivo.J Control Release. 2018 Nov 28;290:1-10. doi: 10.1016/j.jconrel.2018.09.031. Epub 2018 Oct 2.
• [8] Relaxin 2/RXFP1 Signaling Induces Cell Invasion via the -Catenin Pathway in Endometrial Cancer.Int J Mol Sci. 2018 Aug 18;19(8):2438. doi: 10.3390/ijms19082438.
• [9] Human relaxin-2 attenuates hepatic steatosis and fibrosis in mice with non-alcoholic fatty liver disease.Lab Invest. 2019 Jul;99(8):1203-1216. doi: 10.1038/s41374-019-0240-y. Epub 2019 Mar 27.
• [10] Human recombinant relaxin-2 does not attenuate hypertension or renal injury but exacerbates vascular dysfunction in a female mouse model of SLE.Am J Physiol Heart Circ Physiol. 2019 Aug 1;317(2):H234-H242. doi: 10.1152/ajpheart.00174.2019. Epub 2019 May 24.
• [11] Human medullary thyroid carcinoma: a source and potential target for relaxin-like hormones.Ann N Y Acad Sci. 2005 May;1041:449-61. doi: 10.1196/annals.1282.069.
• [12] Opposite actions of urotensin II and relaxin-2 on cellular expression of fibronectin in renal fibrosis: A preliminary experimental study.Clin Exp Pharmacol Physiol. 2017 Oct;44(10):1069-1071. doi: 10.1111/1440-1681.12798. Epub 2017 Aug 24.
• [13] Relaxin enhances the collagenolytic activity and in vitro invasiveness by upregulating matrix metalloproteinases in human thyroid carcinoma cells.Mol Cancer Res. 2011 Jun;9(6):673-87. doi: 10.1158/1541-7786.MCR-10-0411. Epub 2011 Apr 14.
• [14] RLN2 Is a Positive Regulator of AKT-2-Induced Gene Expression Required for Osteosarcoma Cells Invasion and Chemoresistance.Biomed Res Int. 2015;2015:147468. doi: 10.1155/2015/147468. Epub 2015 Jul 1.
• [15] Relaxin 2 fails to lower intraocular pressure and to dilate retinal vessels in rats.Int Ophthalmol. 2019 Apr;39(4):847-851. doi: 10.1007/s10792-018-0884-4. Epub 2018 Mar 13.
• [16] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [17] Cyclosporine A--induced oxidative stress in human renal mesangial cells: a role for ERK 1/2 MAPK signaling. Toxicol Sci. 2012 Mar;126(1):101-13.
• [18] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [19] Estrogen and TCDD influence RLN2 gene activity in estrogen receptor-positive human breast cancer cells. Ann N Y Acad Sci. 2009 Apr;1160:367-73. doi: 10.1111/j.1749-6632.2009.03836.x.
• [20] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [21] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [22] 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.
• [23] 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.