Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTK1PBFD)

• DOT Name: IQ motif and SEC7 domain-containing protein 1 (IQSEC1)
• Synonyms: ADP-ribosylation factors guanine nucleotide-exchange protein 100; ADP-ribosylation factors guanine nucleotide-exchange protein 2; Brefeldin-resistant Arf-GEF 2 protein; BRAG2
• Gene Name: IQSEC1
• Related Disease:
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Head and neck cancer
  Head and neck carcinoma
  Hepatocellular carcinoma
  Intellectual developmental disorder with short stature and behavioral abnormalities
  Lung adenocarcinoma
  Lung cancer
  Lung neoplasm
  Metastatic malignant neoplasm
  Neoplasm
  Intellectual disability
  Autosomal recessive non-syndromic intellectual disability
  Pancreatic cancer
• UniProt ID: IQEC1_HUMAN
• PDB ID: 3QWM; 4C0A; 5NLV; 5NLY; 6FNE; 7VMB
• Pfam ID: PF16453 ; PF01369
• Sequence:
  MWCLHCNSERTQSLLELELDSGVEGEAPSSETGTSLDSPSAYPQGPLVPGSSLSPDHYEH
  TSVGAYGLYSGPPGQQQRTRRPKLQHSTSILRKQAEEEAIKRSRSLSESYELSSDLQDKQ
  VEMLERKYGGRLVTRHAARTIQTAFRQYQMNKNFERLRSSMSENRMSRRIVLSNMRMQFS
  FEGPEKVHSSYFEGKQVSVTNDGSQLGALVSPECGDLSEPTTLKSPAPSSDFADAITELE
  DAFSRQVKSLAESIDDALNCRSLHTEEAPALDAARARDTEPQTALHGMDHRKLDEMTASY
  SDVTLYIDEEELSPPLPLSQAGDRPSSTESDLRLRAGGAAPDYWALAHKEDKADTDTSCR
  STPSLERQEQRLRVEHLPLLTIEPPSDSSVDLSDRSERGSLKRQSAYERSLGGQQGSPKH
  GPHSGAPKSLPREEPELRPRPPRPLDSHLAINGSANRQSKSESDYSDGDNDSINSTSNSN
  DTINCSSESSSRDSLREQTLSKQTYHKEARNSWDSPAFSNDVIRKRHYRIGLNLFNKKPE
  KGVQYLIERGFVPDTPVGVAHFLLQRKGLSRQMIGEFLGNRQKQFNRDVLDCVVDEMDFS
  TMELDEALRKFQAHIRVQGEAQKVERLIEAFSQRYCICNPGVVRQFRNPDTIFILAFAII
  LLNTDMYSPNVKPERKMKLEDFIKNLRGVDDGEDIPREMLMGIYERIRKRELKTNEDHVS
  QVQKVEKLIVGKKPIGSLHPGLGCVLSLPHRRLVCYCRLFEVPDPNKPQKLGLHQREIFL
  FNDLLVVTKIFQKKKNSVTYSFRQSFSLYGMQVLLFENQYYPNGIRLTSSVPGADIKVLI
  NFNAPNPQDRKKFTDDLRESIAEVQEMEKHRIESELEKQKGVVRPSMSQCSSLKKESGNG
  TLSRACLDDSYASGEGLKRSALSSSLRDLSEAGKRGRRSSAGSLESNVEFQPFEPLQPSV
  LCS
• Function: Guanine nucleotide exchange factor for ARF1 and ARF6. Guanine nucleotide exchange factor activity is enhanced by lipid binding. Accelerates GTP binding by ARFs of all three classes. Guanine nucleotide exchange protein for ARF6, mediating internalization of beta-1 integrin. Involved in neuronal development (Probable). In neurons, plays a role in the control of vesicle formation by endocytoc cargo. Upon long term depression, interacts with GRIA2 and mediates the activation of ARF6 to internalize synaptic AMPAR receptors.
• Tissue Specificity: Expressed in brain, ovary, heart, lung, liver, kidney and leukocytes. Moderate expression was also detected in lung, skeletal muscle, placenta, small intestine, pancreas, spleen and testis.
• KEGG Pathway: Endocytosis (hsa04144)

Molecular Interaction Atlas (MIA) of This DOT

16 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Breast cancer	DIS7DPX1	Strong	Biomarker	[2]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[2]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[3]
Head and neck cancer	DISBPSQZ	Strong	Biomarker	[4]
Head and neck carcinoma	DISOU1DS	Strong	Biomarker	[4]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[5]
Intellectual developmental disorder with short stature and behavioral abnormalities	DIS10JIK	Strong	Autosomal recessive	[6]
Lung adenocarcinoma	DISD51WR	Strong	Altered Expression	[7]
Lung cancer	DISCM4YA	Strong	Biomarker	[8]
Lung neoplasm	DISVARNB	Strong	Biomarker	[8]
Metastatic malignant neoplasm	DIS86UK6	Strong	Biomarker	[7]
Neoplasm	DISZKGEW	Strong	Biomarker	[9]
Intellectual disability	DISMBNXP	moderate	Genetic Variation	[10]
Autosomal recessive non-syndromic intellectual disability	DISJWRZZ	Supportive	Autosomal recessive	[10]
Pancreatic cancer	DISJC981	Limited	Altered Expression	[11]

3 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 IQ motif and SEC7 domain-containing protein 1 (IQSEC1).	[12]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of IQ motif and SEC7 domain-containing protein 1 (IQSEC1).	[22]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of IQ motif and SEC7 domain-containing protein 1 (IQSEC1).	[23]

10 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 IQ motif and SEC7 domain-containing protein 1 (IQSEC1).	[13]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of IQ motif and SEC7 domain-containing protein 1 (IQSEC1).	[14]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of IQ motif and SEC7 domain-containing protein 1 (IQSEC1).	[15]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of IQ motif and SEC7 domain-containing protein 1 (IQSEC1).	[16]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of IQ motif and SEC7 domain-containing protein 1 (IQSEC1).	[17]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of IQ motif and SEC7 domain-containing protein 1 (IQSEC1).	[18]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of IQ motif and SEC7 domain-containing protein 1 (IQSEC1).	[19]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of IQ motif and SEC7 domain-containing protein 1 (IQSEC1).	[20]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of IQ motif and SEC7 domain-containing protein 1 (IQSEC1).	[21]
Nickel chloride	DMI12Y8	Investigative	Nickel chloride increases the expression of IQ motif and SEC7 domain-containing protein 1 (IQSEC1).	[24]

References

• [1] Multiple interactions between an Arf/GEF complex and charged lipids determine activation kinetics on the membrane.Proc Natl Acad Sci U S A. 2017 Oct 24;114(43):11416-11421. doi: 10.1073/pnas.1707970114. Epub 2017 Sep 18.
• [2] GEP100 regulates epidermal growth factor-induced MDA-MB-231 breast cancer cell invasion through the activation of Arf6/ERK/uPAR signaling pathway.Exp Cell Res. 2013 Aug 1;319(13):1932-1941. doi: 10.1016/j.yexcr.2013.05.028. Epub 2013 Jun 5.
• [3] GEP100 links epidermal growth factor receptor signalling to Arf6 activation to induce breast cancer invasion.Nat Cell Biol. 2008 Jan;10(1):85-92. doi: 10.1038/ncb1672. Epub 2007 Dec 16.
• [4] Inhibition of epithelial-mesenchymal transition by cetuximab via the EGFR-GEP100-Arf6-AMAP1 pathway in head and neck cancer.Head Neck. 2017 Mar;39(3):476-485. doi: 10.1002/hed.24626. Epub 2016 Nov 23.
• [5] GEP100/Arf6 is required for epidermal growth factor-induced ERK/Rac1 signaling and cell migration in human hepatoma HepG2 cells.PLoS One. 2012;7(6):e38777. doi: 10.1371/journal.pone.0038777. Epub 2012 Jun 11.
• [6] Prevalence and architecture of de novo mutations in developmental disorders. Nature. 2017 Feb 23;542(7642):433-438. doi: 10.1038/nature21062. Epub 2017 Jan 25.
• [7] Engagement of overexpressed Her2 with GEP100 induces autonomous invasive activities and provides a biomarker for metastases of lung adenocarcinoma.PLoS One. 2011;6(9):e25301. doi: 10.1371/journal.pone.0025301. Epub 2011 Sep 22.
• [8] Bronchial airway gene expression signatures in mouse lung squamous cell carcinoma and their modulation by cancer chemopreventive agents.Oncotarget. 2017 Mar 21;8(12):18885-18900. doi: 10.18632/oncotarget.13806.
• [9] Frequent overexpression of AMAP1, an Arf6 effector in cell invasion, is characteristic of the MMTV-PyMT rather than the MMTV-Neu human breast cancer model.Cell Commun Signal. 2018 Jan 5;16(1):1. doi: 10.1186/s12964-017-0212-z.
• [10] Bi-allelic Variants in IQSEC1 Cause Intellectual Disability, Developmental Delay, and Short Stature. Am J Hum Genet. 2019 Nov 7;105(5):907-920. doi: 10.1016/j.ajhg.2019.09.013. Epub 2019 Oct 10.
• [11] Downregulation of GEP100 Improved the Growth Inhibition Effect of Erlotinib Through Modulating Mesenchymal Epithelial Transition Process in Pancreatic Cancer.Pancreas. 2018 Jul;47(6):732-737. doi: 10.1097/MPA.0000000000001076.
• [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] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [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] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [17] 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.
• [18] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [19] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [20] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [21] 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.
• [22] 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.
• [23] 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.
• [24] Zerovalent Fe, Co and Ni nanoparticle toxicity evaluated on SKOV-3 and U87 cell lines. J Appl Toxicol. 2016 Mar;36(3):385-93.