Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT5CSK9X)

• DOT Name: Fibronectin type III domain-containing protein 5 (FNDC5)
• Synonyms: Fibronectin type III repeat-containing protein 2
• Gene Name: FNDC5
• Related Disease:
  Graves disease
  Thyroid gland papillary carcinoma
  Alzheimer disease
  Arteriosclerosis
  Atherosclerosis
  Colorectal carcinoma
  Dementia
  Diabetic kidney disease
  Fatty liver disease
  Hyperlipidemia
  Myocardial fibrosis
  Neoplasm
  Non-alcoholic fatty liver disease
  Non-insulin dependent diabetes
  Non-small-cell lung cancer
  Obesity
  Cardiovascular disease
  Ewing sarcoma
  Hepatocellular carcinoma
  High blood pressure
  Kidney cancer
  Metabolic disorder
  Renal carcinoma
  Renal cell carcinoma
  Rhabdomyosarcoma
  Type-1/2 diabetes
  Cardiomyopathy
  Advanced cancer
  Chronic kidney disease
  Chronic renal failure
  End-stage renal disease
  Neuroblastoma
  Non-alcoholic steatohepatitis
• UniProt ID: FNDC5_HUMAN
• PDB ID: 4LSD
• Pfam ID: PF00041
• Sequence:
  MHPGSPSAWPPRARAALRLWLGCVCFALVQADSPSAPVNVTVRHLKANSAVVSWDVLEDE
  VVIGFAISQQKKDVRMLRFIQEVNTTTRSCALWDLEEDTEYIVHVQAISIQGQSPASEPV
  LFKTPREAEKMASKNKDEVTMKEMGRNQQLRTGEVLIIVVVLFMWAGVIALFCRQYDIIK
  DNEPNNNKEKTKSASETSTPEHQGGGLLRSKI
• Function: [Irisin]: Contrary to mouse, may not be involved in the beneficial effects of muscular exercise, nor in the induction of browning of human white adipose tissue.
• Tissue Specificity: Widely expressed, with highest levels in heart. Very low expression, if any, in colon, pancreas and spleen.

Molecular Interaction Atlas (MIA) of This DOT

33 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Graves disease	DISU4KOQ	Definitive	Altered Expression	[1]
Thyroid gland papillary carcinoma	DIS48YMM	Definitive	Altered Expression	[1]
Alzheimer disease	DISF8S70	Strong	Biomarker	[2]
Arteriosclerosis	DISK5QGC	Strong	Altered Expression	[3]
Atherosclerosis	DISMN9J3	Strong	Altered Expression	[3]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[4]
Dementia	DISXL1WY	Strong	Biomarker	[5]
Diabetic kidney disease	DISJMWEY	Strong	Genetic Variation	[6]
Fatty liver disease	DIS485QZ	Strong	Genetic Variation	[7]
Hyperlipidemia	DIS61J3S	Strong	Altered Expression	[3]
Myocardial fibrosis	DISMOLYU	Strong	Therapeutic	[8]
Neoplasm	DISZKGEW	Strong	Altered Expression	[9]
Non-alcoholic fatty liver disease	DISDG1NL	Strong	Genetic Variation	[7]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Biomarker	[10]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[11]
Obesity	DIS47Y1K	Strong	Altered Expression	[12]
Cardiovascular disease	DIS2IQDX	moderate	Biomarker	[13]
Ewing sarcoma	DISQYLV3	moderate	Biomarker	[14]
Hepatocellular carcinoma	DIS0J828	moderate	Altered Expression	[15]
High blood pressure	DISY2OHH	moderate	Biomarker	[16]
Kidney cancer	DISBIPKM	moderate	Biomarker	[17]
Metabolic disorder	DIS71G5H	moderate	Biomarker	[13]
Renal carcinoma	DISER9XT	moderate	Biomarker	[17]
Renal cell carcinoma	DISQZ2X8	moderate	Biomarker	[17]
Rhabdomyosarcoma	DISNR7MS	moderate	Biomarker	[14]
Type-1/2 diabetes	DISIUHAP	moderate	Biomarker	[13]
Cardiomyopathy	DISUPZRG	Disputed	Biomarker	[18]
Advanced cancer	DISAT1Z9	Limited	Altered Expression	[11]
Chronic kidney disease	DISW82R7	Limited	Altered Expression	[19]
Chronic renal failure	DISGG7K6	Limited	Altered Expression	[19]
End-stage renal disease	DISXA7GG	Limited	Altered Expression	[19]
Neuroblastoma	DISVZBI4	Limited	Altered Expression	[20]
Non-alcoholic steatohepatitis	DIST4788	Limited	Genetic Variation	[21]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Fibronectin type III domain-containing protein 5 (FNDC5).	[22]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Fibronectin type III domain-containing protein 5 (FNDC5).	[23]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Fibronectin type III domain-containing protein 5 (FNDC5).	[24]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Fibronectin type III domain-containing protein 5 (FNDC5).	[25]
Cisplatin	DMRHGI9	Approved	Cisplatin affects the expression of Fibronectin type III domain-containing protein 5 (FNDC5).	[26]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Fibronectin type III domain-containing protein 5 (FNDC5).	[27]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Fibronectin type III domain-containing protein 5 (FNDC5).	[26]
Panobinostat	DM58WKG	Approved	Panobinostat decreases the expression of Fibronectin type III domain-containing protein 5 (FNDC5).	[28]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Fibronectin type III domain-containing protein 5 (FNDC5).	[29]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Fibronectin type III domain-containing protein 5 (FNDC5).	[31]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Fibronectin type III domain-containing protein 5 (FNDC5).	[32]

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 affects the methylation of Fibronectin type III domain-containing protein 5 (FNDC5).	[30]

References

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• [2] Mechanistic complexities of bone loss in Alzheimer's disease: a review.Connect Tissue Res. 2020 Jan;61(1):4-18. doi: 10.1080/03008207.2019.1624734. Epub 2019 Jun 11.
• [3] Irisin Is Controlled by Farnesoid X Receptor and Regulates Cholesterol Homeostasis.Front Pharmacol. 2019 May 28;10:548. doi: 10.3389/fphar.2019.00548. eCollection 2019.
• [4] Serum and Adipose Tissue mRNA Levels of ATF3 and FNDC5/Irisin in Colorectal Cancer Patients With or Without Obesity.Front Physiol. 2018 Sep 10;9:1125. doi: 10.3389/fphys.2018.01125. eCollection 2018.
• [5] Are the neuroprotective effects of exercise training systemically mediated?.Prog Cardiovasc Dis. 2019 Mar-Apr;62(2):94-101. doi: 10.1016/j.pcad.2019.02.003. Epub 2019 Feb 22.
• [6] Association of irisin and FNDC5 rs16835198 G>T gene polymorphism with type 2 diabetes mellitus and diabetic nephropathy. An Egyptian pilot study.Gene. 2017 Aug 30;626:26-31. doi: 10.1016/j.gene.2017.05.010. Epub 2017 May 4.
• [7] A polymorphism in the Irisin-encoding gene (FNDC5) associates with hepatic steatosis by differential miRNA binding to the 3'UTR.J Hepatol. 2019 Mar;70(3):494-500. doi: 10.1016/j.jhep.2018.10.021. Epub 2018 Oct 31.
• [8] Irisin attenuates angiotensin II-induced cardiac fibrosis via Nrf2 mediated inhibition of ROS/ TGF1/Smad2/3 signaling axis.Chem Biol Interact. 2019 Apr 1;302:11-21. doi: 10.1016/j.cbi.2019.01.031. Epub 2019 Jan 29.
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• [10] Association between Irisin, hs-CRP, and Metabolic Status in Children and Adolescents with Type 2 Diabetes Mellitus.Mediators Inflamm. 2019 Mar 20;2019:6737318. doi: 10.1155/2019/6737318. eCollection 2019.
• [11] Expression of Irisin/FNDC5 in Cancer Cells and Stromal Fibroblasts of Non-small Cell Lung Cancer.Cancers (Basel). 2019 Oct 11;11(10):1538. doi: 10.3390/cancers11101538.
• [12] Obesity caused by a high-fat diet regulates the Sirt1/PGC-1/FNDC5/BDNF pathway to exacerbate isoflurane-induced postoperative cognitive dysfunction in older mice.Nutr Neurosci. 2020 Dec;23(12):971-982. doi: 10.1080/1028415X.2019.1581460. Epub 2019 Feb 22.
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• [15] Increased FNDC5/Irisin expression in human hepatocellular carcinoma.Peptides. 2017 Feb;88:62-66. doi: 10.1016/j.peptides.2016.12.014. Epub 2016 Dec 21.
• [16] Fibronectin type III domain containing 5 attenuates NLRP3 inflammasome activation and phenotypic transformation of adventitial fibroblasts in spontaneously hypertensive rats.J Hypertens. 2018 May;36(5):1104-1114. doi: 10.1097/HJH.0000000000001654.
• [17] The Diagnostic Value of FNDC5/Irisin in Renal Cell Cancer.Int Braz J Urol. 2018 Jul-Aug;44(4):734-739. doi: 10.1590/S1677-5538.IBJU.2017.0404.
• [18] FNDC5 alleviates oxidative stress and cardiomyocyte apoptosis in doxorubicin-induced cardiotoxicity via activating AKT.Cell Death Differ. 2020 Feb;27(2):540-555. doi: 10.1038/s41418-019-0372-z. Epub 2019 Jun 17.
• [19] Urotensin II Induces Mice Skeletal Muscle Atrophy Associated with Enhanced Autophagy and Inhibited Irisin Precursor (Fibronectin Type III Domain Containing 5) Expression in Chronic Renal Failure.Kidney Blood Press Res. 2019;44(4):479-495. doi: 10.1159/000499880. Epub 2019 Jun 25.
• [20] PGC-1 or FNDC5 Is Involved in Modulating the Effects of A(1-42) Oligomers on Suppressing the Expression of BDNF, a Beneficial Factor for Inhibiting Neuronal Apoptosis, A Deposition and Cognitive Decline of APP/PS1 Tg Mice.Front Aging Neurosci. 2017 Mar 21;9:65. doi: 10.3389/fnagi.2017.00065. eCollection 2017.
• [21] Fibronectin Type III Domain-Containing Protein 5 rs3480 A>G Polymorphism, Irisin, and Liver Fibrosis in Patients With Nonalcoholic Fatty Liver Disease.J Clin Endocrinol Metab. 2017 Aug 1;102(8):2660-2669. doi: 10.1210/jc.2017-00056.
• [22] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [23] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [24] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [25] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [26] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
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• [29] Gene expression profiling in Ishikawa cells: a fingerprint for estrogen active compounds. Toxicol Appl Pharmacol. 2009 Apr 1;236(1):85-96.
• [30] Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
• [31] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [32] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.