Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT5VIRP2)

• DOT Name: FYVE, RhoGEF and PH domain-containing protein 5 (FGD5)
• Synonyms: Zinc finger FYVE domain-containing protein 23
• Gene Name: FGD5
• Related Disease:
  Aarskog-Scott syndrome, X-linked
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Cardiovascular disease
  High blood pressure
  Psoriasis
  Clear cell renal carcinoma
  Coronary heart disease
  Advanced cancer
  Neoplasm
• UniProt ID: FGD5_HUMAN
• PDB ID: 3MPX
• Pfam ID: PF01363 ; PF00169 ; PF00621
• Sequence:
  MFRGPKPPIAPKPRLTAPNEWRASVYLNDSLNKCSNGRLPCVDRGLDEGPRSIPKCSESE
  TDEDYIVVPRVPLREDEPKDEGSVGNKALVSPESSAEEEEEREEGGEACGLEGTGAGEDS
  VAPAAPGAGALSREGEEGTDLALEDEGEGCADEPGTLEQVSRSEEEEKLVQPHRECSLED
  SGPWAGEGVFQSDLLLPHIHGEDQEPPDTPGEAEEDDEEGCASTDPAGADEGSGPDRPTE
  DMGQDAEDTSEEPPEKEELAGVQEAETATDCPEVLEEGCEEATGVTGGEQVDLSEPPDHE
  KKTNQEVAAATLEDHAQDESAEESCQIVPFENDCMEDFVTSLTGSPYEFFPTESTSFCSE
  SCSPLSESAKGLESEQAPKLGLRAEENPMVGALCGQCGSLQGGAAEGPAAPDVVVVLEEE
  ALDDALANPYVMGVGLPGQAAPGEGGQAASDALGGYGSKEELNCEAEGGLVPADRKNTST
  RVRPHSGKVAGYVPETVPEETGPEAGSSAPGIGGAAEEVGKTLLSLEGKPLEASRALPAK
  PRAFTLYPRSFSVEGREIPVSVYQEPEGSGLDDHRIKRKEDNLSLSCVIGSSGSFSQRNH
  LPSSGTSTPSSMVDIPPPFDLACITKKPITKSSPSLLIESDSPDKYKKKKSSFKRFLALT
  FKKKTENKLHVDVNVSSSRSSSESSYHGPSRILEVDRRSLSNSPQLKSRTGKLRASESPS
  SLIFYRDGKRKGVPFSRTVSRVESFEDRSRPPFLPLPLTKPRSISFPSADTSDYENIPAM
  NSDYENIQIPPRRPARAGAFTKLFEDQSRALSTANENDGYVDMSSFNAFESKQQSADQDA
  ESAYTEPYKVCPISSAAPKEDLTSDEEQRSSEEEDSASRDPSVTHKVEGQSRALVIAQEL
  LSSEKAYVEMLQHLNLDFHGAVMRALDDMDHEGRDTLAREELRQGLSELPAIHDLHQGIL
  EELEERLSNWESQQKVADVFLAREQGFDHHATHILQFDRYLGLLSENCLHSPRLAAAVRE
  FEQSVQGGSQTAKHRLLRVVQRLFQYQVLLTDYLNNLCPDSAEYDNTQGALSLISKVTDR
  ANDSMEQGENLQKLVHIEHSVRGQGDLLQPGREFLKEGTLMKVTGKNRRPRHLFLMNDVL
  LYTYPQKDGKYRLKNTLAVANMKVSRPVMEKVPYALKIETSESCLMLSASSCAERDEWYG
  CLSRALPEDYKAQALAAFHHSVEIRERLGVSLGERPPTLVPVTHVMMCMNCGCDFSLTLR
  RHHCHACGKIVCRNCSRNKYPLKYLKDRMAKVCDGCFGELKKRGRAVPGLMRERPVSMSF
  PLSSPRFSGSAFSSVFQSINPSTFKKQKKVPSALTEVAASGEGSAISGYLSRCKRGKRHW
  KKLWFVIKGKVLYTYMASEDKVALESMPLLGFTIAPEKEEGSSEVGPIFHLYHKKTLFYS
  FKAEDTNSAQRWIEAMEDASVL
• Function: Activates CDC42, a member of the Ras-like family of Rho- and Rac proteins, by exchanging bound GDP for free GTP. Mediates VEGF-induced CDC42 activation. May regulate proangiogenic action of VEGF in vascular endothelial cells, including network formation, directional movement and proliferation. May play a role in regulating the actin cytoskeleton and cell shape.
• Tissue Specificity: Expressed in endothelial cells (at protein level).
• Reactome Pathway: RAC1 GTPase cycle (R-HSA-9013149)

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Aarskog-Scott syndrome, X-linked	DISNHV62	Strong	Genetic Variation	[1]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[1]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[2]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[3]
Cardiovascular disease	DIS2IQDX	Strong	Genetic Variation	[4]
High blood pressure	DISY2OHH	Strong	Genetic Variation	[5]
Psoriasis	DIS59VMN	Strong	Altered Expression	[6]
Clear cell renal carcinoma	DISBXRFJ	moderate	Biomarker	[7]
Coronary heart disease	DIS5OIP1	moderate	Genetic Variation	[8]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[2]
Neoplasm	DISZKGEW	Limited	Biomarker	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of FYVE, RhoGEF and PH domain-containing protein 5 (FGD5).	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of FYVE, RhoGEF and PH domain-containing protein 5 (FGD5).	[10]
Cisplatin	DMRHGI9	Approved	Cisplatin affects the expression of FYVE, RhoGEF and PH domain-containing protein 5 (FGD5).	[11]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of FYVE, RhoGEF and PH domain-containing protein 5 (FGD5).	[11]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of FYVE, RhoGEF and PH domain-containing protein 5 (FGD5).	[12]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of FYVE, RhoGEF and PH domain-containing protein 5 (FGD5).	[12]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of FYVE, RhoGEF and PH domain-containing protein 5 (FGD5).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the mutagenesis of FYVE, RhoGEF and PH domain-containing protein 5 (FGD5).	[14]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of FYVE, RhoGEF and PH domain-containing protein 5 (FGD5).	[15]

References

• [1] Characterization of FGD5 Expression in Primary Breast Cancers and Lymph Node Metastases.J Histochem Cytochem. 2018 Nov;66(11):787-799. doi: 10.1369/0022155418792032. Epub 2018 Jul 27.
• [2] FGD5 amplification in breast cancer patients is associated with tumour proliferation and a poorer prognosis.Breast Cancer Res Treat. 2017 Apr;162(2):243-253. doi: 10.1007/s10549-017-4125-8. Epub 2017 Jan 25.
• [3] An integrated genomics approach identifies drivers of proliferation in luminal-subtype human breast cancer.Nat Genet. 2014 Oct;46(10):1051-9. doi: 10.1038/ng.3073. Epub 2014 Aug 24.
• [4] Leveraging Polygenic Functional Enrichment to Improve GWAS Power.Am J Hum Genet. 2019 Jan 3;104(1):65-75. doi: 10.1016/j.ajhg.2018.11.008. Epub 2018 Dec 27.
• [5] Genetic analyses of diverse populations improves discovery for complex traits.Nature. 2019 Jun;570(7762):514-518. doi: 10.1038/s41586-019-1310-4. Epub 2019 Jun 19.
• [6] Expression of pro-angiogenic genes in mesenchymal stem cells derived from dermis of patients with psoriasis.Int J Dermatol. 2016 May;55(5):e280-8. doi: 10.1111/ijd.13197. Epub 2016 Jan 8.
• [7] Global isoform-specific transcript alterations and deregulated networks in clear cell renal cell carcinoma.Oncotarget. 2018 May 4;9(34):23670-23680. doi: 10.18632/oncotarget.25330. eCollection 2018 May 4.
• [8] 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.
• [9] 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.
• [10] 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.
• [11] 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.
• [12] 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.
• [13] 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.
• [14] Exome-wide mutation profile in benzo[a]pyrene-derived post-stasis and immortal human mammary epithelial cells. Mutat Res Genet Toxicol Environ Mutagen. 2014 Dec;775-776:48-54. doi: 10.1016/j.mrgentox.2014.10.011. Epub 2014 Nov 4.
• [15] 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.