Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTA5B18F)

• DOT Name: UPF0606 protein KIAA1549 (KIAA1549)
• Gene Name: KIAA1549
• Related Disease:
  Central nervous system neoplasm
  Astrocytoma
  Brain neoplasm
  Neoplasm
  Retinitis pigmentosa 86
  Anaplastic astrocytoma
  BAP1-related tumor predisposition syndrome
  Glioma
  Neurofibromatosis type 1
  Oligoastrocytoma
  Retinitis pigmentosa
• UniProt ID: K1549_HUMAN
• Pfam ID: PF12877
• Sequence:
  MPGARRRRRGAAMEGKPRAGVALAPGPSGRRPSARCARRRRPGLLLPGLWLLLLARPASC
  APDELSPEQHNLSLYSMELVLKKSTGHSAAQVALTETAPGSQHSSPLHVTAPPSATTFDT
  AFFNQGKQTKSTADPSIFVATYVSVTSKEVAVNDDEMDNFLPDTHWTTPRMVSPIQYITV
  SPPGLPREALEPMLTPSLPMVSLQDEEVTSGWQNTTRQPAAYAESASHFHTFRSAFRTSE
  GIVPTPGRNLVLYPTDAYSHLSSRTLPEIVASLTEGVETTLFLSSRSLMPQPLGDGITIP
  LPSLGEVSQPPEEVWATSADRYTDVTTVLSQSLEETISPRTYPTVTASHAALAFSRTHSP
  LLSTPLAFASSASPTDVSSNPFLPSDSSKTSELHSNSALPGPVDNTHILSPVSSFRPYTW
  CAACTVPSPQQVLATSLMEKDVGSGDGAETLCMTVLEESSISLMSSVVADFSEFEEDPQV
  FNTLFPSRPIVPLSSRSMEISETSVGISAEVDMSSVTTTQVPPAHGRLSVPASLDPTAGS
  LSVAETQVTPSSVTTAFFSVITSILLDSSFSVIANKNTPSLAVRDPSVFTPYSLVPSVES
  SLFSDQERSSFSEHKPRGALDFASSFFSTPPLELSGSISSPSEAPASLSLMPSDLSPFTS
  QSFSPLVETFTLFDSSDLQSSQLSLPSSTNLEFSQLQPSSELPLNTIMLLPSRSEVSPWS
  SFPSDSLEFVEASTVSLTDSEAHFTSAFIETTSYLESSLISHESAVTALVPPGSESFDIL
  TAGIQATSPLTTVHTTPILTESSLFSTLTPPDDQISALDGHVSVLASFSKAIPTGTVLIT
  DAYLPSGSSFVSEATPFPLPTELTVVGPSLTPTEVPLNTSTEVSTTSTGAATGGPLDSTL
  MGDAASQSPPESSAAPPLPSLRPVTAFTLEATVDTPTLATAKPPYVCDITVPDAYLITTV
  LARRAVQEYIITAIKEVLRIHFNRAVELKVYELFTDFTFLVTSGPFVYTAISVINVLINS
  KLVRDQTPLILSVKPSFLVPESRFQVQTVLQFVPPSVDTGFCNFTQRIEKGLMTALFEVR
  KHHQGTYNLTVQILNITISSSRVTPRRGPVNIIFAVKSTQGFLNGSEVSELLRNLSVVEF
  SFYLGYPVLQIAEPFQYPQLNLSQLLKSSWVRTVLLGVMEKQLQNEVFQAEMERKLAQLL
  SEVSTRRRMWRRATVAAGNSVVQVVNVSRLEGDDNPVQLIYFVEDQDGERLSAVKSSDLI
  NKMDLQRAAIILGYRIQGVIAQPVDRVKRPSPESQSNNLWVIVGVVIPVLVVMVIVVILY
  WKLCRTDKLDFQPDTVANIQQRQKLQIPSVKGFDFAKQHLGQHNKDDILIIHEPAPLPGP
  LKDHTTPSENGDVPSPKSKIPSKNVRHRGRVSPSDADSTVSEESSERDAGDKTPGAVNDG
  RSHRAPQSGPPLPSSGNEQHSSASIFEHVDRISRPPEASRRVPSKIQLIAMQPIPAPPVQ
  RPSPADRVAESNKINKEIQTALRHKSEIEHHRNKIRLRAKRRGHYEFPVVDDLSSGDTKE
  RHRVYRRAQMQIDKILDPTASVPSVFIEPRKSSRIKRSPKPRRKHQVNGCPADAEKDRLI
  TTDSDGTYRRPPGVHNSAYIGCPSDPDLPADVQTPSSVELGRYPALPFPASQYIPPQPSI
  EEARQTMHSLLDDAFALVAPSSQPASTAGVGPGVPPGLPANSTPSQEERRATQWGSFYSP
  AQTANNPCSRYEDYGMTPPTGPLPRPGFGPGLLQSTELVPPDPQQPQASAEAPFAARGIY
  SEEMPSVARPRPVGGTTGSQIQHLTQVGIASRIGAQPVEIPPSRGSQYGGPGWPSYGEDE
  AGRREATHMLGHQEYSSSPLFQVPRTSGREPSAPSGNLPHRGLQGPGLGYPTSSTEDLQP
  GHSSASLIKAIREELLRLSQKQSTVQNFHS
• Function: May play a role in photoreceptor function.
• Tissue Specificity: .Expression is low to moderate in retina and tissues, such as heart and kidney, and is predominantly expressed in brain.; [Isoform 4]: Abundantly expressed in the retina, compared with only minimal expression in brain and other tissues.
• Reactome Pathway: Signaling by BRAF and RAF1 fusions (R-HSA-6802952)

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Central nervous system neoplasm	DISFC18W	Definitive	Altered Expression	[1]
Astrocytoma	DISL3V18	Strong	Genetic Variation	[2]
Brain neoplasm	DISY3EKS	Strong	Genetic Variation	[3]
Neoplasm	DISZKGEW	Strong	Genetic Variation	[4]
Retinitis pigmentosa 86	DISTXQ7Y	Strong	Autosomal recessive	[5]
Anaplastic astrocytoma	DISSBE0K	moderate	Biomarker	[6]
BAP1-related tumor predisposition syndrome	DISO4FCC	moderate	Genetic Variation	[7]
Glioma	DIS5RPEH	moderate	Biomarker	[7]
Neurofibromatosis type 1	DIS53JH9	moderate	Altered Expression	[7]
Oligoastrocytoma	DISQGE8F	moderate	Biomarker	[6]
Retinitis pigmentosa	DISCGPY8	Supportive	Autosomal dominant	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of UPF0606 protein KIAA1549 (KIAA1549).	[9]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of UPF0606 protein KIAA1549 (KIAA1549).	[10]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of UPF0606 protein KIAA1549 (KIAA1549).	[11]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of UPF0606 protein KIAA1549 (KIAA1549).	[12]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of UPF0606 protein KIAA1549 (KIAA1549).	[13]
Marinol	DM70IK5	Approved	Marinol increases the expression of UPF0606 protein KIAA1549 (KIAA1549).	[14]
Menadione	DMSJDTY	Approved	Menadione affects the expression of UPF0606 protein KIAA1549 (KIAA1549).	[15]
Panobinostat	DM58WKG	Approved	Panobinostat decreases the expression of UPF0606 protein KIAA1549 (KIAA1549).	[16]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of UPF0606 protein KIAA1549 (KIAA1549).	[17]
Sodium lauryl sulfate	DMLJ634	Approved	Sodium lauryl sulfate increases the expression of UPF0606 protein KIAA1549 (KIAA1549).	[18]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of UPF0606 protein KIAA1549 (KIAA1549).	[19]

1 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 decreases the methylation of UPF0606 protein KIAA1549 (KIAA1549).	[20]

References

• [1] Analysis of IDH1-R132 mutation, BRAF V600 mutation and KIAA1549-BRAF fusion transcript status in central nervous system tumors supports pediatric tumor classification.J Cancer Res Clin Oncol. 2016 Jan;142(1):89-100. doi: 10.1007/s00432-015-2006-2. Epub 2015 Jun 27.
• [2] Analysis of KIAA1549-BRAF fusion gene expression and IDH1/IDH2 mutations in low grade pediatric astrocytomas.J Neurooncol. 2014 Apr;117(2):235-42. doi: 10.1007/s11060-014-1398-1. Epub 2014 Feb 17.
• [3] Oncogenic BRAF Alterations and Their Role in Brain Tumors.Cancers (Basel). 2019 Jun 8;11(6):794. doi: 10.3390/cancers11060794.
• [4] A Multiplex Quantitative Reverse Transcription Polymerase Chain Reaction Assay for the Detection of KIAA1549-BRAF Fusion Transcripts in Formalin-Fixed Paraffin-Embedded Pilocytic Astrocytomas.Mol Diagn Ther. 2019 Aug;23(4):537-545. doi: 10.1007/s40291-019-00403-3.
• [5] Autozygome-guided exome sequencing in retinal dystrophy patients reveals pathogenetic mutations and novel candidate disease genes. Genome Res. 2013 Feb;23(2):236-47. doi: 10.1101/gr.144105.112. Epub 2012 Oct 26.
• [6] Recurrent somatic alterations of FGFR1 and NTRK2 in pilocytic astrocytoma.Nat Genet. 2013 Aug;45(8):927-32. doi: 10.1038/ng.2682. Epub 2013 Jun 30.
• [7] The molecular and cell biology of pediatric low-grade gliomas.Oncogene. 2014 Apr 17;33(16):2019-26. doi: 10.1038/onc.2013.148. Epub 2013 Apr 29.
• [8] Homozygous variants in KIAA1549, encoding a ciliary protein, are associated with autosomal recessive retinitis pigmentosa. J Med Genet. 2018 Oct;55(10):705-712. doi: 10.1136/jmedgenet-2018-105364. Epub 2018 Aug 17.
• [9] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [10] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [11] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [12] 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.
• [13] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [14] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [15] 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.
• [16] 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.
• [17] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [18] CXCL14 downregulation in human keratinocytes is a potential biomarker for a novel in vitro skin sensitization test. Toxicol Appl Pharmacol. 2020 Jan 1;386:114828. doi: 10.1016/j.taap.2019.114828. Epub 2019 Nov 14.
• [19] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [20] 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.