Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTTRU341)

• DOT Name: Afadin (AFDN)
• Synonyms: ALL1-fused gene from chromosome 6 protein; Protein AF-6; Afadin adherens junction formation factor
• Gene Name: AFDN
• Related Disease:
  Parkinson disease
  Acute monocytic leukemia
  Acute myelogenous leukaemia
  Advanced cancer
  Breast neoplasm
  Cardiac failure
  Colon cancer
  Colon carcinoma
  Congestive heart failure
  Endometrial cancer
  Endometrial carcinoma
  Epithelial ovarian cancer
  Herpes simplex infection
  Myeloid leukaemia
  Ovarian cancer
  Breast cancer
  Breast carcinoma
  Adult glioblastoma
  Emery-Dreifuss muscular dystrophy
  Glioblastoma multiforme
  T-cell acute lymphoblastic leukaemia
• UniProt ID: AFAD_HUMAN
• PDB ID: 1T2M; 1XZ9; 2AIN; 2EXG; 5A6C; 7QCR
• Pfam ID: PF01843 ; PF00498 ; PF00595 ; PF00788
• Sequence:
  MSAGGRDEERRKLADIIHHWNANRLDLFEISQPTEDLEFHGVMRFYFQDKAAGNFATKCI
  RVSSTATTQDVIETLAEKFRPDMRMLSSPKYSLYEVHVSGERRLDIDEKPLVVQLNWNKD
  DREGRFVLKNENDAIPPKKAQSNGPEKQEKEGVIQNFKRTLSKKEKKEKKKREKEALRQA
  SDKDDRPFQGEDVENSRLAAEVYKDMPETSFTRTISNPEVVMKRRRQQKLEKRMQEFRSS
  DGRPDSGGTLRIYADSLKPNIPYKTILLSTTDPADFAVAEALEKYGLEKENPKDYCIARV
  MLPPGAQHSDEKGAKEIILDDDECPLQIFREWPSDKGILVFQLKRRPPDHIPKKTKKHLE
  GKTPKGKERADGSGYGSTLPPEKLPYLVELSPGRRNHFAYYNYHTYEDGSDSRDKPKLYR
  LQLSVTEVGTEKLDDNSIQLFGPGIQPHHCDLTNMDGVVTVTPRSMDAETYVEGQRISET
  TMLQSGMKVQFGASHVFKFVDPSQDHALAKRSVDGGLMVKGPRHKPGIVQETTFDLGGDI
  HSGTALPTSKSTTRLDSDRVSSASSTAERGMVKPMIRVEQQPDYRRQESRTQDASGPELI
  LPASIEFRESSEDSFLSAIINYTNSSTVHFKLSPTYVLYMACRYVLSNQYRPDISPTERT
  HKVIAVVNKMVSMMEGVIQKQKNIAGALAFWMANASELLNFIKQDRDLSRITLDAQDVLA
  HLVQMAFKYLVHCLQSELNNYMPAFLDDPEENSLQRPKIDDVLHTLTGAMSLLRRCRVNA
  ALTIQLFSQLFHFINMWLFNRLVTDPDSGLCSHYWGAIIRQQLGHIEAWAEKQGLELAAD
  CHLSRIVQATTLLTMDKYAPDDIPNINSTCFKLNSLQLQALLQNYHCAPDEPFIPTDLIE
  NVVTVAENTADELARSDGREVQLEEDPDLQLPFLLPEDGYSCDVVRNIPNGLQEFLDPLC
  QRGFCRLIPHTRSPGTWTIYFEGADYESHLLRENTELAQPLRKEPEIITVTLKKQNGMGL
  SIVAAKGAGQDKLGIYVKSVVKGGAADVDGRLAAGDQLLSVDGRSLVGLSQERAAELMTR
  TSSVVTLEVAKQGAIYHGLATLLNQPSPMMQRISDRRGSGKPRPKSEGFELYNNSTQNGS
  PESPQLPWAEYSEPKKLPGDDRLMKNRADHRSSPNVANQPPSPGGKSAYASGTTAKITSV
  STGNLCTEEQTPPPRPEAYPIPTQTYTREYFTFPASKSQDRMAPPQNQWPNYEEKPHMHT
  DSNHSSIAIQRVTRSQEELREDKAYQLERHRIEAAMDRKSDSDMWINQSSSLDSSTSSQE
  HLNHSSKSVTPASTLTKSGPGRWKTPAAIPATPVAVSQPIRTDLPPPPPPPPVHYAGDFD
  GMSMDLPLPPPPSANQIGLPSAQVAAAERRKREEHQRWYEKEKARLEEERERKRREQERK
  LGQMRTQSLNPAPFSPLTAQQMKPEKPSTLQRPQETVIRELQPQQQPRTIERRDLQYITV
  SKEELSSGDSLSPDPWKRDAKEKLEKQQQMHIVDMLSKEIQELQSKPDRSAEESDRLRKL
  MLEWQFQKRLQESKQKDEDDEEEEDDDVDTMLIMQRLEAERRARLQDEERRRQQQLEEMR
  KREAEDRARQEEERRRQEEERTKRDAEEKRRQEEGYYSRLEAERRRQHDEAARRLLEPEA
  PGLCRPPLPRDYEPPSPSPAPGAPPPPPQRNASYLKTQVLSPDSLFTAKFVAYNEEEEEE
  DCSLAGPNSYPGSTGAAVGAHDACRDAKEKRSKSQDADSPGSSGAPENLTFKERQRLFSQ
  GQDVSNKVKASRKLTELENELNTK
• Function: Belongs to an adhesion system, probably together with the E-cadherin-catenin system, which plays a role in the organization of homotypic, interneuronal and heterotypic cell-cell adherens junctions (AJs). Nectin- and actin-filament-binding protein that connects nectin to the actin cytoskeleton. May play a key role in the organization of epithelial structures of the embryonic ectoderm. Essential for the organization of adherens junctions.
• KEGG Pathway:
  Ras sig.ling pathway (hsa04014)
  Rap1 sig.ling pathway (hsa04015)
  cAMP sig.ling pathway (hsa04024)
  Adherens junction (hsa04520)
  Tight junction (hsa04530)
  Leukocyte transendothelial migration (hsa04670)

Molecular Interaction Atlas (MIA) of This DOT

21 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Parkinson disease	DISQVHKL	Definitive	Biomarker	[1]
Acute monocytic leukemia	DIS28NEL	Strong	Biomarker	[2]
Acute myelogenous leukaemia	DISCSPTN	Strong	Biomarker	[3]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[4]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[5]
Cardiac failure	DISDC067	Strong	Biomarker	[6]
Colon cancer	DISVC52G	Strong	Biomarker	[7]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[7]
Congestive heart failure	DIS32MEA	Strong	Biomarker	[6]
Endometrial cancer	DISW0LMR	Strong	Altered Expression	[8]
Endometrial carcinoma	DISXR5CY	Strong	Altered Expression	[8]
Epithelial ovarian cancer	DIS56MH2	Strong	Genetic Variation	[9]
Herpes simplex infection	DISL1SAV	Strong	Biomarker	[10]
Myeloid leukaemia	DISMN944	Strong	Biomarker	[2]
Ovarian cancer	DISZJHAP	Strong	Genetic Variation	[11]
Breast cancer	DIS7DPX1	moderate	Biomarker	[12]
Breast carcinoma	DIS2UE88	moderate	Biomarker	[12]
Adult glioblastoma	DISVP4LU	Limited	Biomarker	[13]
Emery-Dreifuss muscular dystrophy	DISYTPR5	Limited	Altered Expression	[14]
Glioblastoma multiforme	DISK8246	Limited	Biomarker	[13]
T-cell acute lymphoblastic leukaemia	DIS17AI2	Limited	Genetic Variation	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Afadin (AFDN).	[16]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Afadin (AFDN).	[20]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Afadin (AFDN).	[25]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Afadin (AFDN).	[28]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Afadin (AFDN).	[17]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Afadin (AFDN).	[18]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Afadin (AFDN).	[19]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Afadin (AFDN).	[21]
Rofecoxib	DM3P5DA	Approved	Rofecoxib affects the expression of Afadin (AFDN).	[22]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Afadin (AFDN).	[23]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Afadin (AFDN).	[24]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Afadin (AFDN).	[26]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Afadin (AFDN).	[27]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Afadin (AFDN).	[29]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Afadin (AFDN).	[30]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Afadin (AFDN).	[31]

References

• [1] AF-6 Protects Against Dopaminergic Dysfunction and Mitochondrial Abnormalities in Drosophila Models of Parkinson's Disease.Front Cell Neurosci. 2017 Aug 10;11:241. doi: 10.3389/fncel.2017.00241. eCollection 2017.
• [2] MLL-AF6 fusion oncogene sequesters AF6 into the nucleus to trigger RAS activation in myeloid leukemia.Blood. 2014 Jul 10;124(2):263-72. doi: 10.1182/blood-2013-09-525741. Epub 2014 Apr 2.
• [3] The basic helix-loop-helix transcription factor SHARP1 is an oncogenic driver in MLL-AF6 acute myelogenous leukemia.Nat Commun. 2018 Apr 24;9(1):1622. doi: 10.1038/s41467-018-03854-0.
• [4] CLDN6 enhances chemoresistance to ADM via AF-6/ERKs pathway in TNBC cell line MDAMB231.Mol Cell Biochem. 2018 Jun;443(1-2):169-180. doi: 10.1007/s11010-017-3221-8. Epub 2017 Nov 20.
• [5] Correlated break at PARK2/FRA6E and loss of AF-6/Afadin protein expression are associated with poor outcome in breast cancer.Oncogene. 2007 Jan 11;26(2):298-307. doi: 10.1038/sj.onc.1209772. Epub 2006 Jul 3.
• [6] Differential Effects of Myocardial Afadin on Pressure Overload-Induced Compensated Cardiac Hypertrophy.Circ J. 2017 Nov 24;81(12):1862-1870. doi: 10.1253/circj.CJ-17-0394. Epub 2017 Jun 28.
• [7] Disrupted interaction between CFTR and AF-6/afadin aggravates malignant phenotypes of colon cancer.Biochim Biophys Acta. 2014 Mar;1843(3):618-28. doi: 10.1016/j.bbamcr.2013.12.013.
• [8] Loss of AF-6/afadin induces cell invasion, suppresses the formation of glandular structures and might be a predictive marker of resistance to chemotherapy in endometrial cancer.BMC Cancer. 2015 Apr 12;15:275. doi: 10.1186/s12885-015-1286-x.
• [9] AF6 gene on chromosome band 6q27 maps distal to the minimal region of deletion in epithelial ovarian cancer.Genes Chromosomes Cancer. 1995 Nov;14(3):220-2. doi: 10.1002/gcc.2870140311.
• [10] Role of AF6 protein in cell-to-cell spread of Herpes simplex virus 1.FEBS Lett. 2007 Nov 27;581(28):5349-54. doi: 10.1016/j.febslet.2007.10.030. Epub 2007 Oct 29.
• [11] Definition of a commonly deleted region in ovarian cancers to a 300-kb segment of chromosome 6q27.Cancer Res. 1996 Dec 15;56(24):5586-9.
• [12] Afadin cooperates with Claudin-2 to promote breast cancer metastasis.Genes Dev. 2019 Feb 1;33(3-4):180-193. doi: 10.1101/gad.319194.118. Epub 2019 Jan 28.
• [13] PI3K/AKT/Afadin signaling pathway contributes to pathological vascularization in glioblastomas.Oncol Lett. 2018 Feb;15(2):1893-1899. doi: 10.3892/ol.2017.7461. Epub 2017 Nov 21.
• [14] LMO7 exerts an effect on mitosis progression and the spindle assembly checkpoint.Int J Biochem Cell Biol. 2018 Jan;94:22-30. doi: 10.1016/j.biocel.2017.11.006. Epub 2017 Nov 20.
• [15] Analysis of the t(6;11)(q27;q23) in leukemia shows a consistent breakpoint in AF6 in three patients and in the ML-2 cell line.Genes Chromosomes Cancer. 1996 Apr;15(4):206-16. doi: 10.1002/(SICI)1098-2264(199604)15:4<206::AID-GCC2>3.0.CO;2-5.
• [16] 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.
• [17] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [18] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [19] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [20] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [21] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [22] Rofecoxib modulates multiple gene expression pathways in a clinical model of acute inflammatory pain. Pain. 2007 Mar;128(1-2):136-47.
• [23] 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.
• [24] Changes in gene expressions elicited by physiological concentrations of genistein on human endometrial cancer cells. Mol Carcinog. 2006 Oct;45(10):752-63.
• [25] 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.
• [26] 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.
• [27] 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.
• [28] 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.
• [29] 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.
• [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] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.