Details of Drug Off-Target (DOT)

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

• DOT Name: Fibronectin type III domain-containing protein 3B (FNDC3B)
• Synonyms: Factor for adipocyte differentiation 104; HCV NS5A-binding protein 37
• Gene Name: FNDC3B
• Related Disease:
  OPTN-related open angle glaucoma
  Barrett esophagus
  Craniosynostosis
  Esophageal squamous cell carcinoma
  Gastric cancer
  Hepatocellular carcinoma
  Keratoconus
  Lung adenocarcinoma
  Metastatic malignant neoplasm
  Neoplasm
  Open-angle glaucoma
  Promyelocytic leukaemia
  Stomach cancer
  Coronary heart disease
  Advanced cancer
  Carcinoma of liver and intrahepatic biliary tract
  Glioblastoma multiforme
  Liver cancer
  Melanoma
• UniProt ID: FND3B_HUMAN
• Pfam ID: PF00041
• Sequence:
  MYVTMMMTDQIPLELPPLLNGEVAMMPHLVNGDAAQQVILVQVNPGETFTIRAEDGTLQC
  IQGPAEVPMMSPNGSIPPIHVPPGYISQVIEDSTGVRRVVVTPQSPECYPPSYPSAMSPT
  HHLPPYLTHHPHFIHNSHTAYYPPVTGPGDMPPQFFPQHHLPHTIYGEQEIIPFYGMSTY
  ITREDQYSKPPHKKLKDRQIDRQNRLNSPPSSIYKSSCTTVYNGYGKGHSGGSGGGGSGS
  GPGIKKTERRARSSPKSNDSDLQEYELEVKRVQDILSGIEKPQVSNIQARAVVLSWAPPV
  GLSCGPHSGLSFPYSYEVALSDKGRDGKYKIIYSGEELECNLKDLRPATDYHVRVYAMYN
  SVKGSCSEPVSFTTHSCAPECPFPPKLAHRSKSSLTLQWKAPIDNGSKITNYLLEWDEGK
  RNSGFRQCFFGSQKHCKLTKLCPAMGYTFRLAARNDIGTSGYSQEVVCYTLGNIPQMPSA
  PRLVRAGITWVTLQWSKPEGCSPEEVITYTLEIQEDENDNLFHPKYTGEDLTCTVKNLKR
  STQYKFRLTASNTEGKSCPSEVLVCTTSPDRPGPPTRPLVKGPVTSHGFSVKWDPPKDNG
  GSEILKYLLEITDGNSEANQWEVAYSGSATEYTFTHLKPGTLYKLRACCISTGGHSQCSE
  SLPVRTLSIAPGQCRPPRVLGRPKHKEVHLEWDVPASESGCEVSEYSVEMTEPEDVASEV
  YHGPELECTVGNLLPGTVYRFRVRALNDGGYGPYSDVSEITTAAGPPGQCKAPCISCTPD
  GCVLVGWESPDSSGADISEYRLEWGEDEESLELIYHGTDTRFEIRDLLPAAQYCCRLQAF
  NQAGAGPYSELVLCQTPASAPDPVSTLCVLEEEPLDAYPDSPSACLVLNWEEPCNNGSEI
  LAYTIDLGDTSITVGNTTMHVMKDLLPETTYRIRIQAINEIGAGPFSQFIKAKTRPLPPL
  PPRLECAAAGPQSLKLKWGDSNSKTHAAEDIVYTLQLEDRNKRFISIYRGPSHTYKVQRL
  TEFTCYSFRIQAASEAGEGPFSETYTFSTTKSVPPTIKAPRVTQLEGNSCEILWETVPSM
  KGDPVNYILQVLVGRESEYKQVYKGEEATFQISGLQTNTDYRFRVCACRRCLDTSQELSG
  AFSPSAAFVLQRSEVMLTGDMGSLDDPKMKSMMPTDEQFAAIIVLGFATLSILFAFILQY
  FLMK
• Function: May be a positive regulator of adipogenesis.
• Tissue Specificity: Predominantly expressed in white adipose tissue (WAT) especially in the stromal vascular cells. Expressed in adipocyte differentiable 3T3-L1 cells but not in the non-adipogenic cell line NIH-3T3. Expression increased in the early stage of adipogenesis.

Molecular Interaction Atlas (MIA) of This DOT

19 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
OPTN-related open angle glaucoma	DISDR98A	Definitive	Biomarker	[1]
Barrett esophagus	DIS416Y7	Strong	Biomarker	[2]
Craniosynostosis	DIS6J405	Strong	Biomarker	[3]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Biomarker	[4]
Gastric cancer	DISXGOUK	Strong	Altered Expression	[5]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[6]
Keratoconus	DISOONXH	Strong	Genetic Variation	[7]
Lung adenocarcinoma	DISD51WR	Strong	Biomarker	[8]
Metastatic malignant neoplasm	DIS86UK6	Strong	Altered Expression	[9]
Neoplasm	DISZKGEW	Strong	Altered Expression	[10]
Open-angle glaucoma	DISSZEE8	Strong	Biomarker	[11]
Promyelocytic leukaemia	DISYGG13	Strong	Biomarker	[12]
Stomach cancer	DISKIJSX	Strong	Altered Expression	[5]
Coronary heart disease	DIS5OIP1	moderate	Genetic Variation	[13]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[5]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Limited	Biomarker	[14]
Glioblastoma multiforme	DISK8246	Limited	Altered Expression	[10]
Liver cancer	DISDE4BI	Limited	Biomarker	[14]
Melanoma	DIS1RRCY	Limited	Biomarker	[15]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Cyclophosphamide	DM4O2Z7	Approved	Fibronectin type III domain-containing protein 3B (FNDC3B) affects the response to substance of Cyclophosphamide.	[36]

18 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 Fibronectin type III domain-containing protein 3B (FNDC3B).	[16]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Fibronectin type III domain-containing protein 3B (FNDC3B).	[17]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Fibronectin type III domain-containing protein 3B (FNDC3B).	[18]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Fibronectin type III domain-containing protein 3B (FNDC3B).	[19]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Fibronectin type III domain-containing protein 3B (FNDC3B).	[20]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Fibronectin type III domain-containing protein 3B (FNDC3B).	[21]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Fibronectin type III domain-containing protein 3B (FNDC3B).	[22]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Fibronectin type III domain-containing protein 3B (FNDC3B).	[23]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Fibronectin type III domain-containing protein 3B (FNDC3B).	[25]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Fibronectin type III domain-containing protein 3B (FNDC3B).	[26]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Fibronectin type III domain-containing protein 3B (FNDC3B).	[27]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil decreases the expression of Fibronectin type III domain-containing protein 3B (FNDC3B).	[28]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Fibronectin type III domain-containing protein 3B (FNDC3B).	[26]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Fibronectin type III domain-containing protein 3B (FNDC3B).	[30]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Fibronectin type III domain-containing protein 3B (FNDC3B).	[32]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Fibronectin type III domain-containing protein 3B (FNDC3B).	[33]
chloropicrin	DMSGBQA	Investigative	chloropicrin decreases the expression of Fibronectin type III domain-containing protein 3B (FNDC3B).	[34]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of Fibronectin type III domain-containing protein 3B (FNDC3B).	[35]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Fibronectin type III domain-containing protein 3B (FNDC3B).	[24]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Fibronectin type III domain-containing protein 3B (FNDC3B).	[29]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Fibronectin type III domain-containing protein 3B (FNDC3B).	[31]

References

• [1] Genetic Architecture of Primary Open-Angle Glaucoma in Individuals of African Descent: The African Descent and Glaucoma Evaluation Study III.Ophthalmology. 2019 Jan;126(1):38-48. doi: 10.1016/j.ophtha.2018.10.031. Epub 2018 Oct 21.
• [2] Bioinformatic analyses of microRNA-targeted genes and microarray-identified genes correlated with Barrett's esophagus.Cell Cycle. 2018;17(6):792-800. doi: 10.1080/15384101.2018.1431597.
• [3] Two cases with de novo 3q26.31 microdeletion suggest a role for FNDC3B in human craniofacial development.Am J Med Genet A. 2016 Dec;170(12):3276-3281. doi: 10.1002/ajmg.a.37892. Epub 2016 Aug 19.
• [4] Tumor suppressor microRNA-34a inhibits cell migration and invasion by targeting MMP-2/MMP-9/FNDC3B in esophageal squamous cell carcinoma.Int J Oncol. 2017 Jul;51(1):378-388. doi: 10.3892/ijo.2017.4015. Epub 2017 May 19.
• [5] FNDC3B circular RNA promotes the migration and invasion of gastric cancer cells via the regulation of E-cadherin and CD44 expression.J Cell Physiol. 2019 Nov;234(11):19895-19910. doi: 10.1002/jcp.28588. Epub 2019 Apr 8.
• [6] Genome-Wide Association Study Identifies a Genetic Prediction Model for Postoperative Survival in Patients with Hepatocellular Carcinoma.Med Sci Monit. 2019 Apr 4;25:2452-2478. doi: 10.12659/MSM.915511.
• [7] Evaluating the Association between Keratoconus and Reported Genetic Loci in a Han Chinese Population.Ophthalmic Genet. 2015 Jun;36(2):132-6. doi: 10.3109/13816810.2015.1005317. Epub 2015 Feb 12.
• [8] Overexpression of fibronectin type III domain containing 3B is correlated with epithelial-mesenchymal transition and predicts poor prognosis in lung adenocarcinoma.Exp Ther Med. 2019 May;17(5):3317-3326. doi: 10.3892/etm.2019.7370. Epub 2019 Mar 12.
• [9] Up-regulated microRNA-143 transcribed by nuclear factor kappa B enhances hepatocarcinoma metastasis by repressing fibronectin expression.Hepatology. 2009 Aug;50(2):490-9. doi: 10.1002/hep.23008.
• [10] Potential mechanisms of microRNA-129-5p in inhibiting cell processes including viability, proliferation, migration and invasiveness of glioblastoma cells U87 through targeting FNDC3B.Biomed Pharmacother. 2017 Mar;87:405-411. doi: 10.1016/j.biopha.2016.12.100. Epub 2017 Jan 6.
• [11] Genome-wide association analyses identify multiple loci associated with central corneal thickness and keratoconus.Nat Genet. 2013 Feb;45(2):155-63. doi: 10.1038/ng.2506. Epub 2013 Jan 6.
• [12] FNDC3B is another novel partner fused to RARA in the t(3;17)(q26;q21) variant of acute promyelocytic leukemia.Blood. 2017 May 11;129(19):2705-2709. doi: 10.1182/blood-2017-02-767707. Epub 2017 Mar 17.
• [13] Identification of 64 Novel Genetic Loci Provides an Expanded View on the Genetic Architecture of Coronary Artery Disease.Circ Res. 2018 Feb 2;122(3):433-443. doi: 10.1161/CIRCRESAHA.117.312086. Epub 2017 Dec 6.
• [14] NS5ABP37 inhibits liver cancer by impeding lipogenesis and cholesterogenesis.Cancer Sci. 2017 Jan;108(1):12-22. doi: 10.1111/cas.13117.
• [15] FAD104, a Regulator of Adipogenesis and Osteogenesis, Interacts with the C-Terminal Region of STAT3 and Represses Malignant Transformation of Melanoma Cells.Biol Pharm Bull. 2016 May 1;39(5):849-55. doi: 10.1248/bpb.b15-01026. Epub 2016 Mar 4.
• [16] The neuroprotective action of the mood stabilizing drugs lithium chloride and sodium valproate is mediated through the up-regulation of the homeodomain protein Six1. Toxicol Appl Pharmacol. 2009 Feb 15;235(1):124-34.
• [17] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [18] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [19] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [20] 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.
• [21] The thioxotriazole copper(II) complex A0 induces endoplasmic reticulum stress and paraptotic death in human cancer cells. J Biol Chem. 2009 Sep 4;284(36):24306-19.
• [22] Long-term estrogen exposure promotes carcinogen bioactivation, induces persistent changes in gene expression, and enhances the tumorigenicity of MCF-7 human breast cancer cells. Toxicol Appl Pharmacol. 2009 Nov 1;240(3):355-66.
• [23] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [24] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [25] 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.
• [26] 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.
• [27] 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.
• [28] Pharmacogenomic identification of novel determinants of response to chemotherapy in colon cancer. Cancer Res. 2006 Mar 1;66(5):2765-77.
• [29] 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.
• [30] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [31] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [32] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [33] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [34] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
• [35] Persistence of epigenomic effects after recovery from repeated treatment with two nephrocarcinogens. Front Genet. 2018 Dec 3;9:558.
• [36] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.