Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTIH6283)

• DOT Name: FYVE, RhoGEF and PH domain-containing protein 3 (FGD3)
• Synonyms: Zinc finger FYVE domain-containing protein 5
• Gene Name: FGD3
• Related Disease:
  Aarskog-Scott syndrome, X-linked
  Breast cancer
  Breast carcinoma
  Thyroid gland carcinoma
  Osteochondrodysplasia
  Skeletal dysplasia
• UniProt ID: FGD3_HUMAN
• PDB ID: 2COC
• Pfam ID: PF01363 ; PF00169 ; PF00621
• Sequence:
  MESGRGSSTPPGPIAALGMPDTGPGSSSLGKLQALPVGPRAHCGDPVSLAAAGDGSPDIG
  PTGELSGSLKIPNRDSGIDSPSSSVAGENFPCEEGLEAGPSPTVLGAHAEMALDSQVPKV
  TPQEEADSDVGEEPDSENTPQKADKDAGLAQHSGPQKLLHIAQELLHTEETYVKRLHLLD
  QVFCTRLTDAGIPPEVIMGIFSNISSIHRFHGQFLLPELKTRITEEWDTNPRLGDILQKL
  APFLKMYGEYVKNFDRAVGLVSTWTQRSPLFKDVVHSIQKQEVCGNLTLQHHMLEPVQRV
  PRYELLLKDYLKRLPQDAPDRKDAERSLELISTAANHSNAAIRKVEKMHKLLEVYEQLGG
  EEDIVNPANELIKEGQIQKLSAKNGTPQDRHLFLFNSMILYCVPKLRLMGQKFSVREKMD
  ISGLQVQDIVKPNTAHTFIITGRKRSLELQTRTEEEKKEWIQIIQATIEKHKQNSETFKA
  FGGAFSQDEDPSLSPDMPITSTSPVEPVVTTEGSSGAAGLEPRKLSSKTRRDKEKQSCKS
  CGETFNSITKRRHHCKLCGAVICGKCSEFKAENSRQSRVCRDCFLTQPVAPESTEKTPTA
  DPQPSLLCGPLRLSESGETWSEVWAAIPMSDPQVLHLQGGSQDGRLPRTIPLPSCKLSVP
  DPEERLDSGHVWKLQWAKQSWYLSASSAELQQQWLETLSTAAHGDTAQDSPGALQLQVPM
  GAAAP
• Function: Promotes the formation of filopodia. May activate CDC42, a member of the Ras-like family of Rho- and Rac proteins, by exchanging bound GDP for free GTP. Plays a role in regulating the actin cytoskeleton and cell shape.
• KEGG Pathway: Regulation of actin cytoskeleton (hsa04810)
• Reactome Pathway:
  G alpha (12/13) signalling events (R-HSA-416482)
  CDC42 GTPase cycle (R-HSA-9013148)
  NRAGE signals death through JNK (R-HSA-193648)

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Aarskog-Scott syndrome, X-linked	DISNHV62	Definitive	Genetic Variation	[1]
Breast cancer	DIS7DPX1	Strong	Biomarker	[2]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[2]
Thyroid gland carcinoma	DISMNGZ0	Strong	Biomarker	[3]
Osteochondrodysplasia	DIS9SPWW	moderate	Biomarker	[4]
Skeletal dysplasia	DIS5Z8U6	moderate	Biomarker	[4]

14 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 FYVE, RhoGEF and PH domain-containing protein 3 (FGD3).	[5]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of FYVE, RhoGEF and PH domain-containing protein 3 (FGD3).	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of FYVE, RhoGEF and PH domain-containing protein 3 (FGD3).	[8]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of FYVE, RhoGEF and PH domain-containing protein 3 (FGD3).	[9]
Arsenic	DMTL2Y1	Approved	Arsenic increases the expression of FYVE, RhoGEF and PH domain-containing protein 3 (FGD3).	[10]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of FYVE, RhoGEF and PH domain-containing protein 3 (FGD3).	[11]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of FYVE, RhoGEF and PH domain-containing protein 3 (FGD3).	[12]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of FYVE, RhoGEF and PH domain-containing protein 3 (FGD3).	[13]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the expression of FYVE, RhoGEF and PH domain-containing protein 3 (FGD3).	[14]
Ethinyl estradiol	DMODJ40	Approved	Ethinyl estradiol affects the expression of FYVE, RhoGEF and PH domain-containing protein 3 (FGD3).	[15]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of FYVE, RhoGEF and PH domain-containing protein 3 (FGD3).	[17]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of FYVE, RhoGEF and PH domain-containing protein 3 (FGD3).	[19]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of FYVE, RhoGEF and PH domain-containing protein 3 (FGD3).	[20]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of FYVE, RhoGEF and PH domain-containing protein 3 (FGD3).	[21]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the methylation of FYVE, RhoGEF and PH domain-containing protein 3 (FGD3).	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of FYVE, RhoGEF and PH domain-containing protein 3 (FGD3).	[16]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of FYVE, RhoGEF and PH domain-containing protein 3 (FGD3).	[18]

References

• [1] Isolation, characterization, and mapping of the mouse Fgd3 gene, a new Faciogenital Dysplasia (FGD1; Aarskog Syndrome) gene homologue.Gene. 2000 Jan 25;242(1-2):237-47. doi: 10.1016/s0378-1119(99)00518-1.
• [2] Expression of FGD3 gene as prognostic factor in young breast cancer patients.Sci Rep. 2019 Oct 23;9(1):15204. doi: 10.1038/s41598-019-51766-w.
• [3] Follicular thyroid tumors with the PAX8-PPARgamma1 rearrangement display characteristic genetic alterations.Am J Pathol. 2005 Jul;167(1):223-31. doi: 10.1016/s0002-9440(10)62967-7.
• [4] Non-synonymous FGD3 Variant as Positional Candidate for Disproportional Tall Stature Accounting for a Carcass Weight QTL (CW-3) and Skeletal Dysplasia in Japanese Black Cattle.PLoS Genet. 2015 Aug 25;11(8):e1005433. doi: 10.1371/journal.pgen.1005433. eCollection 2015 Aug.
• [5] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [6] 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.
• [7] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [8] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [9] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [10] Arsenic alters transcriptional responses to Pseudomonas aeruginosa infection and decreases antimicrobial defense of human airway epithelial cells. Toxicol Appl Pharmacol. 2017 Sep 15;331:154-163.
• [11] 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.
• [12] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [13] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [14] Cannabidiol enhances cytotoxicity of anti-cancer drugs in human head and neck squamous cell carcinoma. Sci Rep. 2020 Nov 26;10(1):20622. doi: 10.1038/s41598-020-77674-y.
• [15] The genomic response of Ishikawa cells to bisphenol A exposure is dose- and time-dependent. Toxicology. 2010 Apr 11;270(2-3):137-49. doi: 10.1016/j.tox.2010.02.008. Epub 2010 Feb 17.
• [16] 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.
• [17] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [18] 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.
• [19] Environmental pollutant induced cellular injury is reflected in exosomes from placental explants. Placenta. 2020 Jan 1;89:42-49. doi: 10.1016/j.placenta.2019.10.008. Epub 2019 Oct 17.
• [20] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [21] 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.