Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT7KUNTE)

• DOT Name: Insulin-like 3 (INSL3)
• Synonyms: Leydig insulin-like peptide; Ley-I-L; Relaxin-like factor
• Gene Name: INSL3
• Related Disease:
  Adenoma
  Benign prostatic hyperplasia
  Breast fibrocystic disease
  Carcinoma
  Gastric cancer
  Graves disease
  Hyperplasia
  Hypogonadism
  Hypogonadism, male
  Hypospadias
  Klinefelter syndrome
  Langerhans cell histiocytosis
  Medullary thyroid gland carcinoma
  Neoplasm
  Non-hodgkin lymphoma
  Oligospermia
  Osteoporosis
  Ovarian neoplasm
  Pachyonychia congenita 3
  Polycystic ovarian syndrome
  Prostate carcinoma
  Stomach cancer
  Thyroid gland carcinoma
  Thyroid gland undifferentiated (anaplastic) carcinoma
  Thyroid tumor
  Cryptorchidism
  Female hypogonadism
  Testicular cancer
  Type-1/2 diabetes
  Thyroid gland follicular carcinoma
• UniProt ID: INSL3_HUMAN
• PDB ID: 2H8B; 2K6T; 2K6U
• Pfam ID: PF00049
• Sequence:
  MDPRLPAWALVLLGPALVFALGPAPTPEMREKLCGHHFVRALVRVCGGPRWSTEARRPAT
  GGDRELLQWLERRHLLHGLVADSNLTLGPGLQPLPQTSHHHRHHRAAATNPARYCCLSGC
  TQQDLLTLCPY
• Function: Seems to play a role in testicular function. May be a trophic hormone with a role in testicular descent in fetal life. Is a ligand for LGR8 receptor.
• Tissue Specificity: Expressed in prenatal and postnatal Leydig cells. Found as well in the corpus luteum, trophoblast, fetal membranes and breast.
• 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

30 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adenoma	DIS78ZEV	Strong	Altered Expression	[1]
Benign prostatic hyperplasia	DISI3CW2	Strong	Altered Expression	[2]
Breast fibrocystic disease	DISUM7ID	Strong	Biomarker	[3]
Carcinoma	DISH9F1N	Strong	Biomarker	[4]
Gastric cancer	DISXGOUK	Strong	Genetic Variation	[5]
Graves disease	DISU4KOQ	Strong	Biomarker	[4]
Hyperplasia	DISK4DFB	Strong	Biomarker	[6]
Hypogonadism	DISICMNI	Strong	Biomarker	[7]
Hypogonadism, male	DISV1F5R	Strong	Altered Expression	[8]
Hypospadias	DIS48CCP	Strong	Biomarker	[9]
Klinefelter syndrome	DISOUI7W	Strong	Altered Expression	[10]
Langerhans cell histiocytosis	DISDQSW3	Strong	Biomarker	[11]
Medullary thyroid gland carcinoma	DISHBL3K	Strong	Biomarker	[6]
Neoplasm	DISZKGEW	Strong	Biomarker	[2]
Non-hodgkin lymphoma	DISS2Y8A	Strong	Biomarker	[5]
Oligospermia	DIS6YJF3	Strong	Biomarker	[12]
Osteoporosis	DISF2JE0	Strong	Genetic Variation	[13]
Ovarian neoplasm	DISEAFTY	Strong	Altered Expression	[14]
Pachyonychia congenita 3	DISZLC6C	Strong	Altered Expression	[2]
Polycystic ovarian syndrome	DISZ2BNG	Strong	Biomarker	[15]
Prostate carcinoma	DISMJPLE	Strong	Altered Expression	[2]
Stomach cancer	DISKIJSX	Strong	Genetic Variation	[5]
Thyroid gland carcinoma	DISMNGZ0	Strong	Altered Expression	[4]
Thyroid gland undifferentiated (anaplastic) carcinoma	DISYBB1W	Strong	Altered Expression	[4]
Thyroid tumor	DISLVKMD	Strong	Biomarker	[6]
Cryptorchidism	DISYUD2P	Moderate	Autosomal dominant	[16]
Female hypogonadism	DISWASB4	moderate	Biomarker	[17]
Testicular cancer	DIS6HNYO	moderate	Altered Expression	[18]
Type-1/2 diabetes	DISIUHAP	moderate	Altered Expression	[19]
Thyroid gland follicular carcinoma	DISFK2QT	Limited	Altered Expression	[20]

2 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 Insulin-like 3 (INSL3).	[21]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Insulin-like 3 (INSL3).	[28]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Insulin-like 3 (INSL3).	[22]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Insulin-like 3 (INSL3).	[23]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Insulin-like 3 (INSL3).	[24]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Insulin-like 3 (INSL3).	[25]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Insulin-like 3 (INSL3).	[25]
DTI-015	DMXZRW0	Approved	DTI-015 decreases the expression of Insulin-like 3 (INSL3).	[26]
Testosterone Undecanoate	DMZO10Y	Approved	Testosterone Undecanoate decreases the expression of Insulin-like 3 (INSL3).	[27]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Insulin-like 3 (INSL3).	[29]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Insulin-like 3 (INSL3).	[30]
BADGE	DMCK5DG	Investigative	BADGE increases the expression of Insulin-like 3 (INSL3).	[31]

References

• [1] Expression of relaxin-like factor is down-regulated in human testicular Leydig cell neoplasia.Mol Hum Reprod. 1999 Feb;5(2):104-8. doi: 10.1093/molehr/5.2.104.
• [2] INSL3 in the benign hyperplastic and neoplastic human prostate gland. Int J Oncol. 2005 Aug;27(2):307-15.
• [3] Relaxin-like factor (RLF) is differentially expressed in the normal and neoplastic human mammary gland.Cancer. 2000 Dec 1;89(11):2161-8.
• [4] INSL-3 is expressed in human hyperplastic and neoplastic thyrocytes.Int J Oncol. 2003 May;22(5):993-1001.
• [5] Innate immunity and non-Hodgkin's lymphoma (NHL) related genes in a nested case-control study for gastric cancer risk.PLoS One. 2012;7(9):e45274. doi: 10.1371/journal.pone.0045274. Epub 2012 Sep 21.
• [6] 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.
• [7] Biology of insulin-like factor 3 in human reproduction.Hum Reprod Update. 2009 Jul-Aug;15(4):463-76. doi: 10.1093/humupd/dmp011. Epub 2009 Mar 28.
• [8] Protective Role of Testicular Hormone INSL3 From Atrophy and Weakness in Skeletal Muscle.Front Endocrinol (Lausanne). 2018 Sep 28;9:562. doi: 10.3389/fendo.2018.00562. eCollection 2018.
• [9] Phthalate-Induced Fetal Leydig Cell Dysfunction Mediates Male Reproductive Tract Anomalies.Front Pharmacol. 2019 Nov 6;10:1309. doi: 10.3389/fphar.2019.01309. eCollection 2019.
• [10] Negative Association Between Sclerostin and INSL3 in Isolated Human Osteocytes and in Klinefelter Syndrome: New Hints for Testis-Bone Crosstalk.J Clin Endocrinol Metab. 2018 May 1;103(5):2033-2041. doi: 10.1210/jc.2017-02762.
• [11] INSL3 Expression in Leydig Cell Hyperplasia and Leydig Cell Tumors.Appl Immunohistochem Mol Morphol. 2019 Mar;27(3):203-209. doi: 10.1097/PAI.0000000000000567.
• [12] Bone mineral density and testicular failure: evidence for a role of vitamin D 25-hydroxylase in human testis.J Clin Endocrinol Metab. 2011 Apr;96(4):E646-52. doi: 10.1210/jc.2010-1628. Epub 2011 Jan 26.
• [13] Mutations in the insulin-like factor 3 receptor are associated with osteoporosis.J Bone Miner Res. 2008 May;23(5):683-93. doi: 10.1359/jbmr.080204.
• [14] Elevated plasma levels of the novel hormone INSL3 in a woman with metastatic ovarian cancer.Int J Biol Markers. 2007 Apr-Jun;22(2):159-60. doi: 10.1177/172460080702200210.
• [15] Evaluation of the correlation between insulin like factor 3, polycystic ovary syndrome, and ovarian maldescent.Gynecol Endocrinol. 2018 Jun;34(6):481-488. doi: 10.1080/09513590.2017.1416462. Epub 2017 Dec 19.
• [16] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [17] Insulin-like peptide 3 (INSL3) is a major regulator of female reproductive physiology.Hum Reprod Update. 2018 Nov 1;24(6):639-651. doi: 10.1093/humupd/dmy029.
• [18] Expression patterns of DLK1 and INSL3 identify stages of Leydig cell differentiation during normal development and in testicular pathologies, including testicular cancer and Klinefelter syndrome.Hum Reprod. 2014 Aug;29(8):1637-50. doi: 10.1093/humrep/deu124. Epub 2014 Jun 7.
• [19] Directed overexpression of insulin in Leydig cells causes a progressive loss of germ cells.Mol Cell Endocrinol. 2008 Nov 25;295(1-2):79-86. doi: 10.1016/j.mce.2008.07.007. Epub 2008 Jul 23.
• [20] Lysosomal acid hydrolases of the cathepsin family are novel targets of INSL3 in human thyroid carcinoma cells.Ann N Y Acad Sci. 2009 Apr;1160:361-6. doi: 10.1111/j.1749-6632.2009.03832.x.
• [21] 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.
• [22] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [23] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [24] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [25] Estradiol represses insulin-like 3 expression and promoter activity in MA-10 Leydig cells. Toxicology. 2009 Apr 28;258(2-3):101-5. doi: 10.1016/j.tox.2009.01.013. Epub 2009 Jan 20.
• [26] Gene expression profile induced by BCNU in human glioma cell lines with differential MGMT expression. J Neurooncol. 2005 Jul;73(3):189-98.
• [27] Levonorgestrel enhances spermatogenesis suppression by testosterone with greater alteration in testicular gene expression in men. Biol Reprod. 2009 Mar;80(3):484-92.
• [28] 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.
• [29] Differential effects of bisphenol A and diethylstilbestrol on human, rat and mouse fetal leydig cell function. PLoS One. 2012;7(12):e51579. doi: 10.1371/journal.pone.0051579. Epub 2012 Dec 17.
• [30] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.
• [31] Parallel assessment of the effects of bisphenol A and several of its analogs on the adult human testis. Hum Reprod. 2017 Jul 1;32(7):1465-1473. doi: 10.1093/humrep/dex093.