Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTI0T62C)

• DOT Name: FYVE, RhoGEF and PH domain-containing protein 6 (FGD6)
• Synonyms: Zinc finger FYVE domain-containing protein 24
• Gene Name: FGD6
• Related Disease:
  Chronic obstructive pulmonary disease
  Malignant mesothelioma
  Neovascular age-related macular degeneration
  Age-related macular degeneration
  Coronary heart disease
  Endometriosis
• UniProt ID: FGD6_HUMAN
• Pfam ID: PF01363 ; PF00169 ; PF00621
• Sequence:
  MTSAAEIKKPPVAPKPKFVVANNKPAPPPIAPKPDIVISSVPQSTKKMKPAIAPKPKVLK
  TSPVREIGQSPSRKIMLNLEGHKQELAESTDNFNCKYEGNQSNDYISPMCSCSSECIHKL
  GHRENLCVKQLVLEPLEMNENLENSKIDETLTIKTRSKCDLYGEKAKNQGGVVLKASVLE
  EELKDALIHQMPPFISAQKHRPTDSPEMNGGCNSNGQFRIEFADLSPSPSSFEKVPDHHS
  CHLQLPSDECEHFETCQDDSEKSNNCFQSSELEALENGKRSTLISSDGVSKKSEVKDLGP
  LEIHLVPYTPKFPTPKPRKTRTARLLRQKCVDTPSESTEEPGNSDSSSSCLTENSLKINK
  ISVLHQNVLCKQEQVDKMKLGNKSELNMESNSDAQDLVNSQKAMCNETTSFEKMAPSFDK
  DSNLSSDSTTVDGSSMSLAVDEGTGFIRCTVSMSLPKQLKLTCNEHLQSGRNLGVSAPQM
  QKESVIKEENSLRIVPKKPQRHSLPATGVLKKAASEELLEKSSYPSSEEKSSEKSLERNH
  LQHLCAQNRGVSSSFDMPKRASEKPVWKLPHPILPFSGNPEFLKSVTVSSNSEPSTALTK
  PRAKSLSAMDVEKCTKPCKDSTKKNSFKKLLSMKLSICFMKSDFQKFWSKSSQLGDTTTG
  HLSSGEQKGIESDWQGLLVGEEKRSKPIKAYSTENYSLESQKKRKKSRGQTSAANGLRAE
  SLDDQMLSRESSSQAPYKSVTSLCAPEYENIRHYEEIPEYENLPFIMAIRKTQELEWQNS
  SSMEDADANVYEVEEPYEAPDGQLQLGPRHQHSSSGASQEEQNDLGLGDLPSDEEEIINS
  SDEDDVSSESSKGEPDPLEDKQDEDNGMKSKVHHIAKEIMSSEKVFVDVLKLLHIDFRDA
  VAHASRQLGKPVIEDRILNQILYYLPQLYELNRDLLKELEERMLHWTEQQRIADIFVKKG
  PYLKMYSTYIKEFDKNIALLDEQCKKNPGFAAVVREFEMSPRCANLALKHYLLKPVQRIP
  QYRLLLTDYLKNLIEDAGDYRDTQDALAVVIEVANHANDTMKQGDNFQKLMQIQYSLNGH
  HEIVQPGRVFLKEGILMKLSRKVMQPRMFFLFNDALLYTTPVQSGMYKLNNMLSLAGMKV
  RKPTQEAYQNELKIESVERSFILSASSATERDEWLEAISRAIEEYAKKRITFCPSRSLDE
  ADSENKEEVSPLGSKAPIWIPDTRATMCMICTSEFTLTWRRHHCRACGKIVCQACSSNKY
  GLDYLKNQPARVCEHCFQELQKLDHQHSPRIGSPGNHKSPSSALSSVLHSIPSGRKQKKI
  PAALKEVSANTEDSSMSGYLYRSKGNKKPWKHFWFVIKNKVLYTYAASEDVAALESQPLL
  GFTVIQVKDENSESKVFQLLHKNMLFYVFKAEDAHSAQKWIEAFQEGTIL
• Function: May activate CDC42, a member of the Ras-like family of Rho- and Rac proteins, by exchanging bound GDP for free GTP. May play a role in regulating the actin cytoskeleton and cell shape.

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Chronic obstructive pulmonary disease	DISQCIRF	Strong	Genetic Variation	[1]
Malignant mesothelioma	DISTHJGH	Strong	Biomarker	[2]
Neovascular age-related macular degeneration	DIS5S9R7	Strong	Biomarker	[3]
Age-related macular degeneration	DIS0XS2C	moderate	Genetic Variation	[4]
Coronary heart disease	DIS5OIP1	moderate	Genetic Variation	[5]
Endometriosis	DISX1AG8	moderate	Genetic Variation	[6]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Fluorouracil	DMUM7HZ	Approved	FYVE, RhoGEF and PH domain-containing protein 6 (FGD6) affects the response to substance of Fluorouracil.	[20]
Chlorothiazide	DMLHESP	Approved	FYVE, RhoGEF and PH domain-containing protein 6 (FGD6) increases the Neutropenia ADR of Chlorothiazide.	[21]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of FYVE, RhoGEF and PH domain-containing protein 6 (FGD6).	[7]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of FYVE, RhoGEF and PH domain-containing protein 6 (FGD6).	[8]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of FYVE, RhoGEF and PH domain-containing protein 6 (FGD6).	[9]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of FYVE, RhoGEF and PH domain-containing protein 6 (FGD6).	[10]
Quercetin	DM3NC4M	Approved	Quercetin affects the expression of FYVE, RhoGEF and PH domain-containing protein 6 (FGD6).	[11]
Melphalan	DMOLNHF	Approved	Melphalan decreases the expression of FYVE, RhoGEF and PH domain-containing protein 6 (FGD6).	[12]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of FYVE, RhoGEF and PH domain-containing protein 6 (FGD6).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of FYVE, RhoGEF and PH domain-containing protein 6 (FGD6).	[14]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of FYVE, RhoGEF and PH domain-containing protein 6 (FGD6).	[15]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of FYVE, RhoGEF and PH domain-containing protein 6 (FGD6).	[16]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of FYVE, RhoGEF and PH domain-containing protein 6 (FGD6).	[18]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of FYVE, RhoGEF and PH domain-containing protein 6 (FGD6).	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of FYVE, RhoGEF and PH domain-containing protein 6 (FGD6).	[17]

References

• [1] Genetic landscape of chronic obstructive pulmonary disease identifies heterogeneous cell-type and phenotype associations.Nat Genet. 2019 Mar;51(3):494-505. doi: 10.1038/s41588-018-0342-2. Epub 2019 Feb 25.
• [2] MicroRNA and mRNA features of malignant pleural mesothelioma and benign asbestos-related pleural effusion.Biomed Res Int. 2015;2015:635748. doi: 10.1155/2015/635748. Epub 2015 Feb 1.
• [3] A missense variant in FGD6 confers increased risk of polypoidal choroidal vasculopathy.Nat Genet. 2016 Jun;48(6):640-7. doi: 10.1038/ng.3546. Epub 2016 Apr 18.
• [4] New loci and coding variants confer risk for age-related macular degeneration in East Asians.Nat Commun. 2015 Jan 28;6:6063. doi: 10.1038/ncomms7063.
• [5] 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.
• [6] Genome-wide association meta-analysis identifies new endometriosis risk loci.Nat Genet. 2012 Dec;44(12):1355-9. doi: 10.1038/ng.2445. Epub 2012 Oct 28.
• [7] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [8] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [9] 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.
• [10] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [11] 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.
• [12] Bone marrow osteoblast damage by chemotherapeutic agents. PLoS One. 2012;7(2):e30758. doi: 10.1371/journal.pone.0030758. Epub 2012 Feb 17.
• [13] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [14] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [15] BET bromodomain inhibition targets both c-Myc and IL7R in high-risk acute lymphoblastic leukemia. Blood. 2012 Oct 4;120(14):2843-52.
• [16] 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.
• [17] 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.
• [18] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [19] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [20] 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.
• [21] Genome-wide association study of chemotherapeutic agent-induced severe neutropenia/leucopenia for patients in Biobank Japan. Cancer Sci. 2013 Aug;104(8):1074-82. doi: 10.1111/cas.12186. Epub 2013 Jun 10.