Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT0CD2GG)

• DOT Name: FERM domain-containing protein 3 (FRMD3)
• Synonyms: Band 4.1-like protein 4O; Ovary type protein 4.1; 4.1O
• Gene Name: FRMD3
• Related Disease:
  Lung cancer
  Lung carcinoma
  Lung neoplasm
  Neoplasm
  Non-small-cell lung cancer
  Cardiovascular disease
  High blood pressure
  Kidney failure
  Retinopathy
  Type-1/2 diabetes
  Diabetic kidney disease
  Nephropathy
  Chronic renal failure
  End-stage renal disease
  Non-insulin dependent diabetes
• UniProt ID: FRMD3_HUMAN
• Pfam ID: PF08736 ; PF09380 ; PF00373 ; PF09379
• Sequence:
  MFASCHCVPRGRRTMKMIHFRSSSVKSLSQEMRCTIRLLDDSEISCHIQRETKGQFLIDH
  ICNYYSLLEKDYFGIRYVDPEKQRHWLEPNKSIFKQMKTHPPYTMCFRVKFYPHEPLKIK
  EELTRYLLYLQIKRDIFHGRLLCSFSDAAYLGACIVQAELGDYDPDEHPENYISEFEIFP
  KQSQKLERKIVEIHKNELRGQSPPVAEFNLLLKAHTLETYGVDPHPCKDSTGTTTFLGFT
  AAGFVVFQGNKRIHLIKWPDVCKLKFEGKTFYVIGTQKEKKAMLAFHTSTPAACKHLWKC
  GVENQAFYKYAKSSQIKTVSSSKIFFKGSRFRYSGKVAKEVVEASSKIQREPPEVHRANI
  TQSRSSHSLNKQLIINMEPLQPLLPSPSEQEEELPLGEGVPLPKEENISAPLISSSPVKA
  AREYEDPPSEEEDKIKEEPLTISELVYNPSASLLPTPVDDDEIDMLFDCPSRLELEREDT
  DSFEDLEADENAFLIAEEEELKEARRALSWSYDILTGHIRVNPLVKSFSRLLVVGLGLLL
  FVFPLLLLLLESGIDLSFLCEIRQTPEFEQFHYEYYCPLKEWVAGKVHLILYMLGCS
• Function: Putative tumor suppressor gene that may be implicated in the origin and progression of lung cancer.
• Tissue Specificity: Ovary-specific.

Molecular Interaction Atlas (MIA) of This DOT

15 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Lung cancer	DISCM4YA	Definitive	Biomarker	[1]
Lung carcinoma	DISTR26C	Definitive	Biomarker	[1]
Lung neoplasm	DISVARNB	Definitive	Biomarker	[1]
Neoplasm	DISZKGEW	Definitive	Biomarker	[1]
Non-small-cell lung cancer	DIS5Y6R9	Definitive	Altered Expression	[1]
Cardiovascular disease	DIS2IQDX	Strong	Biomarker	[2]
High blood pressure	DISY2OHH	Strong	Genetic Variation	[3]
Kidney failure	DISOVQ9P	Strong	Genetic Variation	[4]
Retinopathy	DISB4B0F	Strong	Biomarker	[2]
Type-1/2 diabetes	DISIUHAP	Strong	Biomarker	[2]
Diabetic kidney disease	DISJMWEY	moderate	Biomarker	[5]
Nephropathy	DISXWP4P	moderate	Genetic Variation	[5]
Chronic renal failure	DISGG7K6	Disputed	Biomarker	[6]
End-stage renal disease	DISXA7GG	Disputed	Biomarker	[6]
Non-insulin dependent diabetes	DISK1O5Z	Disputed	Biomarker	[6]

19 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 FERM domain-containing protein 3 (FRMD3).	[7]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of FERM domain-containing protein 3 (FRMD3).	[8]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of FERM domain-containing protein 3 (FRMD3).	[9]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of FERM domain-containing protein 3 (FRMD3).	[10]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of FERM domain-containing protein 3 (FRMD3).	[11]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of FERM domain-containing protein 3 (FRMD3).	[12]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of FERM domain-containing protein 3 (FRMD3).	[13]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of FERM domain-containing protein 3 (FRMD3).	[14]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of FERM domain-containing protein 3 (FRMD3).	[15]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of FERM domain-containing protein 3 (FRMD3).	[16]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of FERM domain-containing protein 3 (FRMD3).	[18]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of FERM domain-containing protein 3 (FRMD3).	[8]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of FERM domain-containing protein 3 (FRMD3).	[19]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of FERM domain-containing protein 3 (FRMD3).	[20]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of FERM domain-containing protein 3 (FRMD3).	[21]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of FERM domain-containing protein 3 (FRMD3).	[22]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of FERM domain-containing protein 3 (FRMD3).	[23]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of FERM domain-containing protein 3 (FRMD3).	[24]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A increases the expression of FERM domain-containing protein 3 (FRMD3).	[25]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of FERM domain-containing protein 3 (FRMD3).	[17]

References

• [1] FRMD3, a novel putative tumour suppressor in NSCLC.Oncogene. 2007 Jun 28;26(30):4464-8. doi: 10.1038/sj.onc.1210225. Epub 2007 Jan 29.
• [2] Genetics of diabetes complications.Mamm Genome. 2014 Oct;25(9-10):384-400. doi: 10.1007/s00335-014-9543-x. Epub 2014 Aug 29.
• [3] Single-trait and multi-trait genome-wide association analyses identify novel loci for blood pressure in African-ancestry populations.PLoS Genet. 2017 May 12;13(5):e1006728. doi: 10.1371/journal.pgen.1006728. eCollection 2017 May.
• [4] Differential effects of MYH9 and APOL1 risk variants on FRMD3 Association with Diabetic ESRD in African Americans.PLoS Genet. 2011 Jun;7(6):e1002150. doi: 10.1371/journal.pgen.1002150. Epub 2011 Jun 16.
• [5] Evaluation of associations between single nucleotide polymorphisms in the FRMD3 and CARS genes and diabetic nephropathy in a Kuwaiti population.Genet Mol Res. 2016 Jan 29;15(1). doi: 10.4238/gmr.15017619.
• [6] Evaluation of candidate nephropathy susceptibility genes in a genome-wide association study of African American diabetic kidney disease.PLoS One. 2014 Feb 13;9(2):e88273. doi: 10.1371/journal.pone.0088273. eCollection 2014.
• [7] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [8] 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.
• [9] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [10] 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.
• [11] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [12] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [13] 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.
• [14] 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.
• [15] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [16] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [17] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [18] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
• [19] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [20] 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.
• [21] Comparison of transcriptome expression alterations by chronic exposure to low-dose bisphenol A in different subtypes of breast cancer cells. Toxicol Appl Pharmacol. 2019 Dec 15;385:114814. doi: 10.1016/j.taap.2019.114814. Epub 2019 Nov 9.
• [22] 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.
• [23] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [24] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [25] Persistence of epigenomic effects after recovery from repeated treatment with two nephrocarcinogens. Front Genet. 2018 Dec 3;9:558.