Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTOQK0WK)

• DOT Name: Fibronectin type III domain-containing protein 4 (FNDC4)
• Synonyms: Fibronectin type III repeat-containing protein 1
• Gene Name: FNDC4
• Related Disease:
  Gout
  Hyperlipidemia
  Inflammatory bowel disease
  Non-insulin dependent diabetes
  Colitis
  Lysosomal lipid storage disorder
• UniProt ID: FNDC4_HUMAN
• Pfam ID: PF00041
• Sequence:
  MPSGCHSSPPSGLRGDMASLVPLSPYLSPTVLLLVSCDLGFVRADRPPSPVNVTVTHLRA
  NSATVSWDVPEGNIVIGYSISQQRQNGPGQRVIREVNTTTRACALWGLAEDSDYTVQVRS
  IGLRGESPPGPRVHFRTLKGSDRLPSNSSSPGDITVEGLDGERPLQTGEVVIIVVVLLMW
  AAVIGLFCRQYDIIKDNDSNNNPKEKGKGPEQSPQGRPVGTRQKKSPSINTIDV
• Function: Acts as an anti-inflammatory factor in the intestine and colon. Binds to and acts on macrophages to down-regulate pro-inflammatory gene expression. Affects key macrophage functions, including phagocytosis, by down-regulating many key pathways for macrophage activation, partly via by STAT3 activation and signaling. May be required to dampen the immunological response in colitis.
• Tissue Specificity: Up-regulated in colon cells of patients with inflammatory bowel disease (IBD).

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Gout	DISHC0U7	Strong	Genetic Variation	[1]
Hyperlipidemia	DIS61J3S	Strong	Biomarker	[2]
Inflammatory bowel disease	DISGN23E	Strong	Biomarker	[3]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Biomarker	[2]
Colitis	DISAF7DD	Limited	Biomarker	[4]
Lysosomal lipid storage disorder	DISXQRTX	Limited	Biomarker	[5]

2 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 Fibronectin type III domain-containing protein 4 (FNDC4).	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Fibronectin type III domain-containing protein 4 (FNDC4).	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Fibronectin type III domain-containing protein 4 (FNDC4).	[7]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Fibronectin type III domain-containing protein 4 (FNDC4).	[8]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Fibronectin type III domain-containing protein 4 (FNDC4).	[9]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Fibronectin type III domain-containing protein 4 (FNDC4).	[10]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of Fibronectin type III domain-containing protein 4 (FNDC4).	[11]
Clozapine	DMFC71L	Approved	Clozapine increases the expression of Fibronectin type III domain-containing protein 4 (FNDC4).	[12]
Haloperidol	DM96SE0	Approved	Haloperidol increases the expression of Fibronectin type III domain-containing protein 4 (FNDC4).	[5]
Fluoxetine	DM3PD2C	Approved	Fluoxetine increases the expression of Fibronectin type III domain-containing protein 4 (FNDC4).	[12]
Sertraline	DM0FB1J	Approved	Sertraline increases the expression of Fibronectin type III domain-containing protein 4 (FNDC4).	[12]
Tetracycline	DMZA017	Approved	Tetracycline increases the expression of Fibronectin type III domain-containing protein 4 (FNDC4).	[5]
Thioridazine	DM35M8J	Approved	Thioridazine increases the expression of Fibronectin type III domain-containing protein 4 (FNDC4).	[12]
Imipramine	DM2NUH3	Approved	Imipramine increases the expression of Fibronectin type III domain-containing protein 4 (FNDC4).	[12]
Clomipramine	DMINRKW	Approved	Clomipramine decreases the expression of Fibronectin type III domain-containing protein 4 (FNDC4).	[5]
Erythromycin	DM4K7GQ	Approved	Erythromycin decreases the expression of Fibronectin type III domain-containing protein 4 (FNDC4).	[5]
Pentamidine	DMHZJCG	Approved	Pentamidine increases the expression of Fibronectin type III domain-containing protein 4 (FNDC4).	[12]
Flecainide	DMSQDLE	Approved	Flecainide decreases the expression of Fibronectin type III domain-containing protein 4 (FNDC4).	[5]
Perhexiline	DMINO7Z	Approved	Perhexiline increases the expression of Fibronectin type III domain-containing protein 4 (FNDC4).	[12]
Chlorpromazine	DMBGZI3	Phase 3 Trial	Chlorpromazine increases the expression of Fibronectin type III domain-containing protein 4 (FNDC4).	[12]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Fibronectin type III domain-containing protein 4 (FNDC4).	[5]
Chlorcyclizine	DM3L52Q	Phase 1	Chlorcyclizine increases the expression of Fibronectin type III domain-containing protein 4 (FNDC4).	[12]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Fibronectin type III domain-containing protein 4 (FNDC4).	[15]
ZIMELIDINE	DMNI3U2	Withdrawn from market	ZIMELIDINE increases the expression of Fibronectin type III domain-containing protein 4 (FNDC4).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Fibronectin type III domain-containing protein 4 (FNDC4).	[16]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Fibronectin type III domain-containing protein 4 (FNDC4).	[17]

References

• [1] Genome-wide association analyses identify 18 new loci associated with serum urate concentrations. Nat Genet. 2013 Feb;45(2):145-54. doi: 10.1038/ng.2500. Epub 2012 Dec 23.
• [2] Fibronectin Type III Domain Containing 4 attenuates hyperlipidemia-induced insulin resistance via suppression of inflammation and ER stress through HO-1 expression in adipocytes.Biochem Biophys Res Commun. 2018 Jul 7;502(1):129-136. doi: 10.1016/j.bbrc.2018.05.133. Epub 2018 May 24.
• [3] FNDC4 acts as an anti-inflammatory factor on macrophages and improves colitis in mice.Nat Commun. 2016 Apr 12;7:11314. doi: 10.1038/ncomms11314.
• [4] FNDC4 Inhibits RANKL-Induced Osteoclast Formation by Suppressing NF-B Activation and CXCL10 Expression.Biomed Res Int. 2018 May 30;2018:3936257. doi: 10.1155/2018/3936257. eCollection 2018.
• [5] Determination of phospholipidosis potential based on gene expression analysis in HepG2 cells. Toxicol Sci. 2007 Mar;96(1):101-14.
• [6] 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.
• [7] 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.
• [8] 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.
• [9] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [10] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [11] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [12] A toxicogenomic approach to drug-induced phospholipidosis: analysis of its induction mechanism and establishment of a novel in vitro screening system. Toxicol Sci. 2005 Feb;83(2):282-92.
• [13] Determination of phospholipidosis potential based on gene expression analysis in HepG2 cells. Toxicol Sci. 2007 Mar;96(1):101-14.
• [14] 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.
• [15] 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.
• [16] 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.
• [17] Cystathionine metabolic enzymes play a role in the inflammation resolution of human keratinocytes in response to sub-cytotoxic formaldehyde exposure. Toxicol Appl Pharmacol. 2016 Nov 1;310:185-194.