Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTOWIB9Z)

DOT Name HEAT repeat-containing protein 1 (HEATR1)
Synonyms Protein BAP28; U3 small nucleolar RNA-associated protein 10 homolog
Gene Name HEATR1
Related Disease
Advanced cancer ( )
Glioblastoma multiforme ( )
Glioma ( )
Matthew-Wood syndrome ( )
Neoplasm ( )
Non-small-cell lung cancer ( )
Pancreatic cancer ( )
UniProt ID
HEAT1_HUMAN
3D Structure
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2D Sequence (FASTA)
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3D Structure (PDB)
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PDB ID
7MQ8; 7MQ9; 7MQA
Pfam ID
PF08146 ; PF12397
Sequence
MTSLAQQLQRLALPQSDASLLSRDEVASLLFDPKEAATIDRDTAFAIGCTGLEELLGIDP
SFEQFEAPLFSQLAKTLERSVQTKAVNKQLDENISLFLIHLSPYFLLKPAQKCLEWLIHR
FHIHLYNQDSLIACVLPYHETRIFVRVIQLLKINNSKHRWFWLLPVKQSGVPLAKGTLIT
HCYKDLGFMDFICSLVTKSVKVFAEYPGSSAQLRVLLAFYASTIVSALVAAEDVSDNIIA
KLFPYIQKGLKSSLPDYRAATYMIICQISVKVTMENTFVNSLASQIIKTLTKIPSLIKDG
LSCLIVLLQRQKPESLGKKPFPHLCNVPDLITILHGISETYDVSPLLHYMLPHLVVSIIH
HVTGEETEGMDGQIYKRHLEAILTKISLKNNLDHLLASLLFEEYISYSSQEEMDSNKVSL
LNEQFLPLIRLLESKYPRTLDVVLEEHLKEIADLKKQELFHQFVSLSTSGGKYQFLADSD
TSLMLSLNHPLAPVRILAMNHLKKIMKTSKEGVDESFIKEAVLARLGDDNIDVVLSAISA
FEIFKEHFSSEVTISNLLNLFQRAELSKNGEWYEVLKIAADILIKEEILSENDQLSNQVV
VCLLPFMVINNDDTESAEMKIAIYLSKSGICSLHPLLRGWEEALENVIKSTKPGKLIGVA
NQKMIELLADNINLGDPSSMLKMVEDLISVGEEESFNLKQKVTFHVILSVLVSCCSSLKE
THFPFAIRVFSLLQKKIKKLESVITAVEIPSEWHIELMLDRGIPVELWAHYVEELNSTQR
VAVEDSVFLVFSLKKFIYALKAPKSFPKGDIWWNPEQLKEDSRDYLHLLIGLFEMMLNGA
DAVHFRVLMKLFIKVHLEDVFQLFKFCSVLWTYGSSLSNPLNCSVKTVLQTQALYVGCAM
LSSQKTQCKHQLASISSPVVTSLLINLGSPVKEVRRAAIQCLQALSGVASPFYLIIDHLI
SKAEEITSDAAYVIQDLATLFEELQREKKLKSHQKLSETLKNLLSCVYSCPSYIAKDLMK
VLQGVNGEMVLSQLLPMAEQLLEKIQKEPTAVLKDEAMVLHLTLGKYNEFSVSLLNEDPK
SLDIFIKAVHTTKELYAGMPTIQITALEKITKPFFAAISDEKVQQKLLRMLFDLLVNCKN
SHCAQTVSSVFKGISVNAEQVRIELEPPDKAKPLGTVQQKRRQKMQQKKSQDLESVQEVG
GSYWQRVTLILELLQHKKKLRSPQILVPTLFNLLSRCLEPLPQEQGNMEYTKQLILSCLL
NICQKLSPDGGKIPKDILDEEKFNVELIVQCIRLSEMPQTHHHALLLLGTVAGIFPDKVL
HNIMSIFTFMGANVMRLDDTYSFQVINKTVKMVIPALIQSDSGDSIEVSRNVEEIVVKII
SVFVDALPHVPEHRRLPILVQLVDTLGAEKFLWILLILLFEQYVTKTVLAAAYGEKDAIL
EADTEFWFSVCCEFSVQHQIQSLMNILQYLLKLPEEKEETIPKAVSFNKSESQEEMLQVF
NVETHTSKQLRHFKFLSVSFMSQLLSSNNFLKKVVESGGPEILKGLEERLLETVLGYISA
VAQSMERNADKLTVKFWRALLSKAYDLLDKVNALLPTETFIPVIRGLVGNPLPSVRRKAL
DLLNNKLQQNISWKKTIVTRFLKLVPDLLAIVQRKKKEGEEEQAINRQTALYTLKLLCKN
FGAENPDPFVPVLNTAVKLIAPERKEEKNVLGSALLCIAEVTSTLEALAIPQLPSLMPSL
LTTMKNTSELVSSEVYLLSALAALQKVVETLPHFISPYLEGILSQVIHLEKITSEMGSAS
QANIRLTSLKKTLATTLAPRVLLPAIKKTYKQIEKNWKNHMGPFMSILQEHIGVMKKEEL
TSHQSQLTAFFLEALDFRAQHSENDLEEVGKTENCIIDCLVAMVVKLSEVTFRPLFFKLF
DWAKTEDAPKDRLLTFYNLADCIAEKLKGLFTLFAGHLVKPFADTLNQVNISKTDEAFFD
SENDPEKCCLLLQFILNCLYKIFLFDTQHFISKERAEALMMPLVDQLENRLGGEEKFQER
VTKHLIPCIAQFSVAMADDSLWKPLNYQILLKTRDSSPKVRFAALITVLALAEKLKENYI
VLLPESIPFLAELMEDECEEVEHQCQKTIQQLETVLGEPLQSYF
Function
Ribosome biogenesis factor. Involved in nucleolar processing of pre-18S ribosomal RNA. Required for optimal pre-ribosomal RNA transcription by RNA polymerase I. Part of the small subunit (SSU) processome, first precursor of the small eukaryotic ribosomal subunit. During the assembly of the SSU processome in the nucleolus, many ribosome biogenesis factors, an RNA chaperone and ribosomal proteins associate with the nascent pre-rRNA and work in concert to generate RNA folding, modifications, rearrangements and cleavage as well as targeted degradation of pre-ribosomal RNA by the RNA exosome.
KEGG Pathway
Ribosome biogenesis in eukaryotes (hsa03008 )
Reactome Pathway
Major pathway of rRNA processing in the nucleolus and cytosol (R-HSA-6791226 )
rRNA modification in the nucleus and cytosol (R-HSA-6790901 )

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT
Disease Name Disease ID Evidence Level Mode of Inheritance REF
Advanced cancer DISAT1Z9 Strong Biomarker [1]
Glioblastoma multiforme DISK8246 Strong Biomarker [2]
Glioma DIS5RPEH Strong Biomarker [2]
Matthew-Wood syndrome DISA7HR7 Strong Biomarker [3]
Neoplasm DISZKGEW Strong Biomarker [4]
Non-small-cell lung cancer DIS5Y6R9 Strong Altered Expression [4]
Pancreatic cancer DISJC981 Limited Biomarker [5]
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⏷ Show the Full List of 7 Disease(s)
Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This DOT
18 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 HEAT repeat-containing protein 1 (HEATR1). [6]
Ciclosporin DMAZJFX Approved Ciclosporin increases the expression of HEAT repeat-containing protein 1 (HEATR1). [7]
Tretinoin DM49DUI Approved Tretinoin decreases the expression of HEAT repeat-containing protein 1 (HEATR1). [8]
Acetaminophen DMUIE76 Approved Acetaminophen decreases the expression of HEAT repeat-containing protein 1 (HEATR1). [9]
Cisplatin DMRHGI9 Approved Cisplatin decreases the expression of HEAT repeat-containing protein 1 (HEATR1). [10]
Estradiol DMUNTE3 Approved Estradiol increases the expression of HEAT repeat-containing protein 1 (HEATR1). [11]
Ivermectin DMDBX5F Approved Ivermectin decreases the expression of HEAT repeat-containing protein 1 (HEATR1). [12]
Quercetin DM3NC4M Approved Quercetin decreases the expression of HEAT repeat-containing protein 1 (HEATR1). [13]
Hydrogen peroxide DM1NG5W Approved Hydrogen peroxide affects the expression of HEAT repeat-containing protein 1 (HEATR1). [14]
Vorinostat DMWMPD4 Approved Vorinostat decreases the expression of HEAT repeat-containing protein 1 (HEATR1). [15]
Menadione DMSJDTY Approved Menadione affects the expression of HEAT repeat-containing protein 1 (HEATR1). [14]
Urethane DM7NSI0 Phase 4 Urethane decreases the expression of HEAT repeat-containing protein 1 (HEATR1). [16]
PMID28460551-Compound-2 DM4DOUB Patented PMID28460551-Compound-2 increases the expression of HEAT repeat-containing protein 1 (HEATR1). [18]
Geldanamycin DMS7TC5 Discontinued in Phase 2 Geldanamycin increases the expression of HEAT repeat-containing protein 1 (HEATR1). [20]
Torcetrapib DMDHYM7 Discontinued in Phase 2 Torcetrapib increases the expression of HEAT repeat-containing protein 1 (HEATR1). [21]
Bisphenol A DM2ZLD7 Investigative Bisphenol A decreases the expression of HEAT repeat-containing protein 1 (HEATR1). [22]
Trichostatin A DM9C8NX Investigative Trichostatin A decreases the expression of HEAT repeat-containing protein 1 (HEATR1). [23]
Formaldehyde DM7Q6M0 Investigative Formaldehyde decreases the expression of HEAT repeat-containing protein 1 (HEATR1). [24]
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⏷ Show the Full List of 18 Drug(s)
1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT
Drug Name Drug ID Highest Status Interaction REF
DNCB DMDTVYC Phase 2 DNCB affects the binding of HEAT repeat-containing protein 1 (HEATR1). [17]
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1 Drug(s) Affected the Post-Translational Modifications of This DOT
Drug Name Drug ID Highest Status Interaction REF
PMID28870136-Compound-52 DMFDERP Patented PMID28870136-Compound-52 decreases the phosphorylation of HEAT repeat-containing protein 1 (HEATR1). [19]
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References

1 Perturbation of RNA Polymerase I transcription machinery by ablation of HEATR1 triggers the RPL5/RPL11-MDM2-p53 ribosome biogenesis stress checkpoint pathway in human cells.Cell Cycle. 2018;17(1):92-101. doi: 10.1080/15384101.2017.1403685. Epub 2017 Dec 10.
2 Glioma-associated antigen HEATR1 induces functional cytotoxic T lymphocytes in patients with glioma.J Immunol Res. 2014;2014:131494. doi: 10.1155/2014/131494. Epub 2014 Jul 9.
3 HEATR1 Negatively Regulates Akt to Help Sensitize Pancreatic Cancer Cells to Chemotherapy.Cancer Res. 2016 Feb 1;76(3):572-81. doi: 10.1158/0008-5472.CAN-15-0671. Epub 2015 Dec 16.
4 HEATR1 modulates cell survival in non-small cell lung cancer via activation of the p53/PUMA signaling pathway.Onco Targets Ther. 2019 May 21;12:4001-4011. doi: 10.2147/OTT.S195826. eCollection 2019.
5 HEATR1 deficiency promotes pancreatic cancer proliferation and gemcitabine resistance by up-regulating Nrf2 signaling.Redox Biol. 2020 Jan;29:101390. doi: 10.1016/j.redox.2019.101390. Epub 2019 Nov 20.
6 Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
7 Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
8 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.
9 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.
10 Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
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 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.
13 Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
14 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.
15 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.
16 Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
17 Proteomic analysis of the cellular response to a potent sensitiser unveils the dynamics of haptenation in living cells. Toxicology. 2020 Dec 1;445:152603. doi: 10.1016/j.tox.2020.152603. Epub 2020 Sep 28.
18 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.
19 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.
20 Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
21 Clarifying off-target effects for torcetrapib using network pharmacology and reverse docking approach. BMC Syst Biol. 2012 Dec 10;6:152.
22 Low-dose Bisphenol A exposure alters the functionality and cellular environment in a human cardiomyocyte model. Environ Pollut. 2023 Oct 15;335:122359. doi: 10.1016/j.envpol.2023.122359. Epub 2023 Aug 9.
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 Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.