Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTJDTIK2)

• DOT Name: FERM domain-containing protein 4A (FRMD4A)
• Gene Name: FRMD4A
• Related Disease:
  Alzheimer disease
  Breast carcinoma
  Cholelithiasis
  Craniofacial microsomia
  Drug dependence
  Neoplasm
  Nicotine dependence
  Severe intellectual disability-corpus callosum agenesis-facial dysmorphism-cerebellar ataxia syndrome
  Substance abuse
  Substance dependence
  Phospholipid syndrome
  Acute myelogenous leukaemia
  Basal cell carcinoma
  Basal cell neoplasm
• UniProt ID: FRM4A_HUMAN
• Pfam ID: PF11819 ; PF09380 ; PF00373 ; PF09379
• Sequence:
  MAVQLVPDSALGLLMMTEGRRCQVHLLDDRKLELLVQPKLLAKELLDLVASHFNLKEKEY
  FGIAFTDETGHLNWLQLDRRVLEHDFPKKSGPVVLYFCVRFYIESISYLKDNATIELFFL
  NAKSCIYKELIDVDSEVVFELASYILQEAKGDFSSNEVVRSDLKKLPALPTQALKEHPSL
  AYCEDRVIEHYKKLNGQTRGQAIVNYMSIVESLPTYGVHYYAVKDKQGIPWWLGLSYKGI
  FQYDYHDKVKPRKIFQWRQLENLYFREKKFSVEVHDPRRASVTRRTFGHSGIAVHTWYAC
  PALIKSIWAMAISQHQFYLDRKQSKSKIHAARSLSEIAIDLTETGTLKTSKLANMGSKGK
  IISGSSGSLLSSGSQESDSSQSAKKDMLAALKSRQEALEETLRQRLEELKKLCLREAELT
  GKLPVEYPLDPGEEPPIVRRRIGTAFKLDEQKILPKGEEAELERLEREFAIQSQITEAAR
  RLASDPNVSKKLKKQRKTSYLNALKKLQEIENAINENRIKSGKKPTQRASLIIDDGNIAS
  EDSSLSDALVLEDEDSQVTSTISPLHSPHKGLPPRPPSHNRPPPPQSLEGLRQMHYHRND
  YDKSPIKPKMWSESSLDEPYEKVKKRSSHSHSSSHKRFPSTGSCAEAGGGSNSLQNSPIR
  GLPHWNSQSSMPSTPDLRVRSPHYVHSTRSVDISPTRLHSLALHFRHRSSSLESQGKLLG
  SENDTGSPDFYTPRTRSSNGSDPMDDCSSCTSHSSSEHYYPAQMNANYSTLAEDSPSKAR
  QRQRQRQRAAGALGSASSGSMPNLAARGGAGGAGGAGGGVYLHSQSQPSSQYRIKEYPLY
  IEGGATPVVVRSLESDQEGHYSVKAQFKTSNSYTAGGLFKESWRGGGGDEGDTGRLTPSR
  SQILRTPSLGREGAHDKGAGRAAVSDELRQWYQRSTASHKEHSRLSHTSSTSSDSGSQYS
  TSSQSTFVAHSRVTRMPQMCKATSAALPQSQRSSTPSSEIGATPPSSPHHILTWQTGEAT
  ENSPILDGSESPPHQSTDE
• Function: Scaffolding protein that regulates epithelial cell polarity by connecting ARF6 activation with the PAR3 complex. Plays a redundant role with FRMD4B in epithelial polarization. May regulate MAPT secretion by activating ARF6-signaling.

Molecular Interaction Atlas (MIA) of This DOT

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Alzheimer disease	DISF8S70	Strong	Biomarker	[1]
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[2]
Cholelithiasis	DISERLZB	Strong	Genetic Variation	[3]
Craniofacial microsomia	DISYHJ2P	Strong	Genetic Variation	[4]
Drug dependence	DIS9IXRC	Strong	Biomarker	[5]
Neoplasm	DISZKGEW	Strong	Altered Expression	[6]
Nicotine dependence	DISZD9W7	Strong	Genetic Variation	[7]
Severe intellectual disability-corpus callosum agenesis-facial dysmorphism-cerebellar ataxia syndrome	DIS4QU6X	Strong	Autosomal recessive	[8]
Substance abuse	DIS327VW	Strong	Biomarker	[5]
Substance dependence	DISDRAAR	Strong	Biomarker	[5]
Phospholipid syndrome	DISPI49U	moderate	Genetic Variation	[9]
Acute myelogenous leukaemia	DISCSPTN	Limited	Genetic Variation	[10]
Basal cell carcinoma	DIS7PYN3	Limited	Genetic Variation	[11]
Basal cell neoplasm	DIS37IXW	Limited	Genetic Variation	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Topotecan	DMP6G8T	Approved	FERM domain-containing protein 4A (FRMD4A) affects the response to substance of Topotecan.	[33]

4 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 FERM domain-containing protein 4A (FRMD4A).	[12]
Arsenic	DMTL2Y1	Approved	Arsenic increases the methylation of FERM domain-containing protein 4A (FRMD4A).	[17]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of FERM domain-containing protein 4A (FRMD4A).	[26]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the methylation of FERM domain-containing protein 4A (FRMD4A).	[29]

19 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 FERM domain-containing protein 4A (FRMD4A).	[13]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of FERM domain-containing protein 4A (FRMD4A).	[14]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of FERM domain-containing protein 4A (FRMD4A).	[15]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of FERM domain-containing protein 4A (FRMD4A).	[16]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of FERM domain-containing protein 4A (FRMD4A).	[18]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of FERM domain-containing protein 4A (FRMD4A).	[19]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of FERM domain-containing protein 4A (FRMD4A).	[20]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of FERM domain-containing protein 4A (FRMD4A).	[21]
Menadione	DMSJDTY	Approved	Menadione affects the expression of FERM domain-containing protein 4A (FRMD4A).	[19]
Dexamethasone	DMMWZET	Approved	Dexamethasone decreases the expression of FERM domain-containing protein 4A (FRMD4A).	[22]
Melphalan	DMOLNHF	Approved	Melphalan decreases the expression of FERM domain-containing protein 4A (FRMD4A).	[23]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of FERM domain-containing protein 4A (FRMD4A).	[24]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of FERM domain-containing protein 4A (FRMD4A).	[25]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of FERM domain-containing protein 4A (FRMD4A).	[20]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of FERM domain-containing protein 4A (FRMD4A).	[27]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of FERM domain-containing protein 4A (FRMD4A).	[28]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of FERM domain-containing protein 4A (FRMD4A).	[30]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of FERM domain-containing protein 4A (FRMD4A).	[31]
crotylaldehyde	DMTWRQI	Investigative	crotylaldehyde decreases the expression of FERM domain-containing protein 4A (FRMD4A).	[32]

References

• [1] Transcriptomics and mechanistic elucidation of Alzheimer's disease risk genes in the brain and in vitro models.Neurobiol Aging. 2015 Feb;36(2):1221.e15-28. doi: 10.1016/j.neurobiolaging.2014.09.003. Epub 2014 Sep 6.
• [2] Association analysis identifies 65 new breast cancer risk loci.Nature. 2017 Nov 2;551(7678):92-94. doi: 10.1038/nature24284. Epub 2017 Oct 23.
• [3] A genome-wide association scan identifies the hepatic cholesterol transporter ABCG8 as a susceptibility factor for human gallstone disease.Nat Genet. 2007 Aug;39(8):995-9. doi: 10.1038/ng2101. Epub 2007 Jul 15.
• [4] Genome-wide association study identifies multiple susceptibility loci for craniofacial microsomia.Nat Commun. 2016 Feb 8;7:10605. doi: 10.1038/ncomms10605.
• [5] Genome wide association for addiction: replicated results and comparisons of two analytic approaches.PLoS One. 2010 Jan 21;5(1):e8832. doi: 10.1371/journal.pone.0008832.
• [6] FRMD4A: A potential therapeutic target for the treatment of tongue squamous cell carcinoma.Int J Mol Med. 2016 Nov;38(5):1443-1449. doi: 10.3892/ijmm.2016.2745. Epub 2016 Sep 21.
• [7] Large-scale genome-wide association study of Asian population reveals genetic factors in FRMD4A and other loci influencing smoking initiation and nicotine dependence.Hum Genet. 2012 Jun;131(6):1009-21. doi: 10.1007/s00439-011-1102-x. Epub 2011 Oct 18.
• [8] A syndrome of congenital microcephaly, intellectual disability and dysmorphism with a homozygous mutation in FRMD4A. Eur J Hum Genet. 2015 Dec;23(12):1729-34. doi: 10.1038/ejhg.2014.241. Epub 2014 Nov 12.
• [9] The first genome-wide association study identifying new susceptibility loci for obstetric antiphospholipid syndrome.J Hum Genet. 2017 Sep;62(9):831-838. doi: 10.1038/jhg.2017.46. Epub 2017 Apr 20.
• [10] Genome-wide haplotype association study identify the FGFR2 gene as a risk gene for acute myeloid leukemia.Oncotarget. 2017 Jan 31;8(5):7891-7899. doi: 10.18632/oncotarget.13631.
• [11] Combined analysis of keratinocyte cancers identifies novel genome-wide loci.Hum Mol Genet. 2019 Sep 15;28(18):3148-3160. doi: 10.1093/hmg/ddz121.
• [12] 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.
• [13] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [14] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [15] 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.
• [16] The thioxotriazole copper(II) complex A0 induces endoplasmic reticulum stress and paraptotic death in human cancer cells. J Biol Chem. 2009 Sep 4;284(36):24306-19.
• [17] Association of Arsenic Exposure with Whole Blood DNA Methylation: An Epigenome-Wide Study of Bangladeshi Adults. Environ Health Perspect. 2019 May;127(5):57011. doi: 10.1289/EHP3849. Epub 2019 May 28.
• [18] 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.
• [19] 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.
• [20] 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.
• [21] Coordinate up-regulation of TMEM97 and cholesterol biosynthesis genes in normal ovarian surface epithelial cells treated with progesterone: implications for pathogenesis of ovarian cancer. BMC Cancer. 2007 Dec 11;7:223.
• [22] Genistein disrupts glucocorticoid receptor signaling in human uterine endometrial Ishikawa cells. Environ Health Perspect. 2015 Jan;123(1):80-7. doi: 10.1289/ehp.1408437. Epub 2014 Aug 19.
• [23] Bone marrow osteoblast damage by chemotherapeutic agents. PLoS One. 2012;7(2):e30758. doi: 10.1371/journal.pone.0030758. Epub 2012 Feb 17.
• [24] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [25] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [26] 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.
• [27] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [28] 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.
• [29] 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.
• [30] 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.
• [31] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [32] Gene expression profile and cytotoxicity of human bronchial epithelial cells exposed to crotonaldehyde. Toxicol Lett. 2010 Aug 16;197(2):113-22.
• [33] 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.