Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTV3T64P)

• DOT Name: FYVE, RhoGEF and PH domain-containing protein 1 (FGD1)
• Synonyms: Faciogenital dysplasia 1 protein; Rho/Rac guanine nucleotide exchange factor FGD1; Rho/Rac GEF; Zinc finger FYVE domain-containing protein 3
• Gene Name: FGD1
• Related Disease:
  Aarskog-Scott syndrome, X-linked
  Anxiety
  Anxiety disorder
  Breast cancer
  Breast carcinoma
  Cleft palate
  Congenital nervous system disorder
  Depression
  Isolated cleft palate
  Trichohepatoenteric syndrome
  X-linked intellectual disability
  Addison disease
  Attention deficit hyperactivity disorder
  Familial glucocorticoid deficiency
  Primary adrenal insufficiency
  Rheumatoid arthritis
  Advanced cancer
  Ankylosing spondylitis
  Bone osteosarcoma
  Conduct disorder
  Neoplasm
  Osteosarcoma
  Prostate neoplasm
• UniProt ID: FGD1_HUMAN
• Pfam ID: PF01363 ; PF00169 ; PF00621
• Sequence:
  MHGHRAPGGAGPSEPEHPATNPPGAAPPACADSDPGASEPGLLARRGSGSALGGPLDPQF
  VGPSDTSLGAAPGHRVLPCGPSPQHHRALRFSYHLEGSQPRPGLHQGNRILVKSLSLDPG
  QSLEPHPEGPQRLRSDPGPPTETPSQRPSPLKRAPGPKPQVPPKPSYLQMPRMPPPLEPI
  PPPPSRPLPADPRVAKGLAPRAEASPSSAAVSSLIEKFEREPVIVASDRPVPGPSPGPPE
  PVMLPQPTSQPPVPQLPEGEASRCLFLLAPGPRDGEKVPNRDSGIDSISSPSNSEETCFV
  SDDGPPSHSLCPGPPALASVPVALADPHRPGSQEVDSDLEEEDDEEEEEEKDREIPVPLM
  ERQESVELTVQQKVFHIANELLQTEKAYVSRLHLLDQVFCARLLEEARNRSSFPADVVHG
  IFSNICSIYCFHQQFLLPELEKRMEEWDRYPRIGDILQKLAPFLKMYGEYVKNFDRAVEL
  VNTWTERSTQFKVIIHEVQKEEACGNLTLQHHMLEPVQRIPRYELLLKDYLLKLPHGSPD
  SKDAQKSLELIATAAEHSNAAIRKMERMHKLLKVYELLGGEEDIVSPTKELIKEGHILKL
  SAKNGTTQDRYLILFNDRLLYCVPRLRLLGQKFSVRARIDVDGMELKESSNLNLPRTFLV
  SGKQRSLELQARTEEEKKDWVQAINSTLLKHEQTLETFKLLNSTNREDEDTPPNSPNVDL
  GKRAPTPIREKEVTMCMRCQEPFNSITKRRHHCKACGHVVCGKCSEFRARLVYDNNRSNR
  VCTDCYVALHGVPGSSPACSQHTPQRRRSILEKQASVAAENSVICSFLHYMEKGGKGWHK
  AWFVVPENEPLVLYIYGAPQDVKAQRSLPLIGFEVGPPEAGERPDRRHVFKITQSHLSWY
  FSPETEELQRRWMAVLGRAGRGDTFCPGPTLSEDREMEEAPVAALGATAEPPESPQTRDK
  T
• Function: Activates 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.
• Tissue Specificity: Expressed in fetal heart, brain, lung, kidney and placenta. Less expressed in liver; adult heart, brain, lung, pancreas and skeletal muscle.
• 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

23 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Aarskog-Scott syndrome, X-linked	DISNHV62	Definitive	X-linked	[1]
Anxiety	DISIJDBA	Strong	Biomarker	[2]
Anxiety disorder	DISBI2BT	Strong	Biomarker	[2]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[3]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[3]
Cleft palate	DIS6G5TF	Strong	Genetic Variation	[4]
Congenital nervous system disorder	DIS2BIP8	Strong	Biomarker	[5]
Depression	DIS3XJ69	Strong	Biomarker	[2]
Isolated cleft palate	DISV80CD	Strong	Genetic Variation	[4]
Trichohepatoenteric syndrome	DISL3ODF	Strong	Biomarker	[6]
X-linked intellectual disability	DISYJBY3	Strong	Genetic Variation	[7]
Addison disease	DIS7HNOH	moderate	Genetic Variation	[8]
Attention deficit hyperactivity disorder	DISL8MX9	moderate	Genetic Variation	[9]
Familial glucocorticoid deficiency	DISG7TB4	moderate	Genetic Variation	[8]
Primary adrenal insufficiency	DISNMBYU	moderate	Genetic Variation	[8]
Rheumatoid arthritis	DISTSB4J	Disputed	Biomarker	[10]
Advanced cancer	DISAT1Z9	Limited	Genetic Variation	[11]
Ankylosing spondylitis	DISRC6IR	Limited	Genetic Variation	[12]
Bone osteosarcoma	DIST1004	Limited	Biomarker	[13]
Conduct disorder	DISOLUZ1	Limited	Genetic Variation	[14]
Neoplasm	DISZKGEW	Limited	Biomarker	[15]
Osteosarcoma	DISLQ7E2	Limited	Biomarker	[13]
Prostate neoplasm	DISHDKGQ	Limited	Altered Expression	[11]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Topotecan	DMP6G8T	Approved	FYVE, RhoGEF and PH domain-containing protein 1 (FGD1) affects the response to substance of Topotecan.	[22]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of FYVE, RhoGEF and PH domain-containing protein 1 (FGD1).	[16]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of FYVE, RhoGEF and PH domain-containing protein 1 (FGD1).	[17]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of FYVE, RhoGEF and PH domain-containing protein 1 (FGD1).	[19]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of FYVE, RhoGEF and PH domain-containing protein 1 (FGD1).	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of FYVE, RhoGEF and PH domain-containing protein 1 (FGD1).	[18]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of FYVE, RhoGEF and PH domain-containing protein 1 (FGD1).	[21]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of FYVE, RhoGEF and PH domain-containing protein 1 (FGD1).	[21]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [2] Somatic effects of AAS abuse: A 30-years follow-up study of male former power sports athletes.J Sci Med Sport. 2017 Sep;20(9):814-818. doi: 10.1016/j.jsams.2017.03.008. Epub 2017 Mar 21.
• [3] Faciogenital dysplasia protein Fgd1 regulates invadopodia biogenesis and extracellular matrix degradation and is up-regulated in prostate and breast cancer.Cancer Res. 2009 Feb 1;69(3):747-52. doi: 10.1158/0008-5472.CAN-08-1980. Epub 2009 Jan 13.
• [4] A complex Xp11.22 deletion in a patient with syndromic autism: exploration of FAM120C as a positional candidate gene for autism.Am J Med Genet A. 2014 Dec;164A(12):3035-41. doi: 10.1002/ajmg.a.36752. Epub 2014 Sep 24.
• [5] Two novel mutations confirm FGD1 is responsible for the Aarskog syndrome.Eur J Hum Genet. 2000 Nov;8(11):869-74. doi: 10.1038/sj.ejhg.5200553.
• [6] A novel mutation in a mother and a son with Aarskog-Scott syndrome.J Pediatr Endocrinol Metab. 2013;26(3-4):385-8. doi: 10.1515/jpem-2012-0233.
• [7] Non-syndromic X-linked mental retardation associated with a missense mutation (P312L) in the FGD1 gene.Clin Genet. 2002 Feb;61(2):139-45. doi: 10.1034/j.1399-0004.2002.610209.x.
• [8] Severe loss-of-function mutations in the adrenocorticotropin receptor (ACTHR, MC2R) can be found in patients diagnosed with salt-losing adrenal hypoplasia.Clin Endocrinol (Oxf). 2007 Feb;66(2):205-10. doi: 10.1111/j.1365-2265.2006.02709.x.
• [9] Aarskog-Scott syndrome: a novel mutation in the FGD1 gene associated with severe craniofacial dysplasia.Eur J Pediatr. 2014 Oct;173(10):1373-6. doi: 10.1007/s00431-014-2317-3. Epub 2014 Apr 27.
• [10] A Retrospective Analysis of Subaxial Subluxation After Atlanto-axial Arthrodesis in Patients With Rheumatoid Arthritis Based on Annual Radiographs Obtained for 5 Years.Clin Spine Surg. 2017 Jun;30(5):E598-E602. doi: 10.1097/BSD.0000000000000277.
• [11] Minireview: Role of genetic changes of faciogenital dysplasia protein 1 in human disease.Physiol Genomics. 2016 Jul 1;48(7):446-54. doi: 10.1152/physiolgenomics.00101.2015. Epub 2016 May 6.
• [12] HLA-B27 polymorphism in patients with juvenile and adult-onset ankylosing spondylitis in Southern China.Tissue Antigens. 2010 Jan;75(1):56-60. doi: 10.1111/j.1399-0039.2009.01406.x.
• [13] Skeletal-specific expression of Fgd1 during bone formation and skeletal defects in faciogenital dysplasia (FGDY; Aarskog syndrome).Dev Dyn. 2000 Aug;218(4):573-86. doi: 10.1002/1097-0177(2000)9999:9999<::AID-DVDY1015>3.0.CO;2-F.
• [14] Should childhood conduct disorder be necessary to diagnose antisocial personality disorder in adults?.Ann Clin Psychiatry. 2019 Feb;31(1):36-44.
• [15] FGD1 as a central regulator of extracellular matrix remodelling--lessons from faciogenital dysplasia.J Cell Sci. 2012 Jul 15;125(Pt 14):3265-70. doi: 10.1242/jcs.093419. Epub 2012 Aug 1.
• [16] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [17] 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.
• [18] 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.
• [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] 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.
• [22] 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.