Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTH0OP1J)

• DOT Name: Serine/threonine-protein kinase ATR (ATR)
• Synonyms: EC 2.7.11.1; Ataxia telangiectasia and Rad3-related protein; FRAP-related protein 1
• Gene Name: ATR
• Related Disease:
  Seckel syndrome 1
  Familial cutaneous telangiectasia and oropharyngeal predisposition cancer syndrome
  Sarcoma
  Seckel syndrome
• UniProt ID: ATR_HUMAN
• PDB ID: 5YZ0
• EC Number: 2.7.11.1
• Pfam ID: PF02259 ; PF02260 ; PF00454 ; PF08064
• Sequence:
  MGEHGLELASMIPALRELGSATPEEYNTVVQKPRQILCQFIDRILTDVNVVAVELVKKTD
  SQPTSVMLLDFIQHIMKSSPLMFVNVSGSHEAKGSCIEFSNWIITRLLRIAATPSCHLLH
  KKICEVICSLLFLFKSKSPAIFGVLTKELLQLFEDLVYLHRRNVMGHAVEWPVVMSRFLS
  QLDEHMGYLQSAPLQLMSMQNLEFIEVTLLMVLTRIIAIVFFRRQELLLWQIGCVLLEYG
  SPKIKSLAISFLTELFQLGGLPAQPASTFFSSFLELLKHLVEMDTDQLKLYEEPLSKLIK
  TLFPFEAEAYRNIEPVYLNMLLEKLCVMFEDGVLMRLKSDLLKAALCHLLQYFLKFVPAG
  YESALQVRKVYVRNICKALLDVLGIEVDAEYLLGPLYAALKMESMEIIEEIQCQTQQENL
  SSNSDGISPKRRRLSSSLNPSKRAPKQTEEIKHVDMNQKSILWSALKQKAESLQISLEYS
  GLKNPVIEMLEGIAVVLQLTALCTVHCSHQNMNCRTFKDCQHKSKKKPSVVITWMSLDFY
  TKVLKSCRSLLESVQKLDLEATIDKVVKIYDALIYMQVNSSFEDHILEDLCGMLSLPWIY
  SHSDDGCLKLTTFAANLLTLSCRISDSYSPQAQSRCVFLLTLFPRRIFLEWRTAVYNWAL
  QSSHEVIRASCVSGFFILLQQQNSCNRVPKILIDKVKDDSDIVKKEFASILGQLVCTLHG
  MFYLTSSLTEPFSEHGHVDLFCRNLKATSQHECSSSQLKASVCKPFLFLLKKKIPSPVKL
  AFIDNLHHLCKHLDFREDETDVKAVLGTLLNLMEDPDKDVRVAFSGNIKHILESLDSEDG
  FIKELFVLRMKEAYTHAQISRNNELKDTLILTTGDIGRAAKGDLVPFALLHLLHCLLSKS
  ASVSGAAYTEIRALVAAKSVKLQSFFSQYKKPICQFLVESLHSSQMTALPNTPCQNADVR
  KQDVAHQREMALNTLSEIANVFDFPDLNRFLTRTLQVLLPDLAAKASPAASALIRTLGKQ
  LNVNRREILINNFKYIFSHLVCSCSKDELERALHYLKNETEIELGSLLRQDFQGLHNELL
  LRIGEHYQQVFNGLSILASFASSDDPYQGPRDIISPELMADYLQPKLLGILAFFNMQLLS
  SSVGIEDKKMALNSLMSLMKLMGPKHVSSVRVKMMTTLRTGLRFKDDFPELCCRAWDCFV
  RCLDHACLGSLLSHVIVALLPLIHIQPKETAAIFHYLIIENRDAVQDFLHEIYFLPDHPE
  LKKIKAVLQEYRKETSESTDLQTTLQLSMKAIQHENVDVRIHALTSLKETLYKNQEKLIK
  YATDSETVEPIISQLVTVLLKGCQDANSQARLLCGECLGELGAIDPGRLDFSTTETQGKD
  FTFVTGVEDSSFAYGLLMELTRAYLAYADNSRAQDSAAYAIQELLSIYDCREMETNGPGH
  QLWRRFPEHVREILEPHLNTRYKSSQKSTDWSGVKKPIYLSKLGSNFAEWSASWAGYLIT
  KVRHDLASKIFTCCSIMMKHDFKVTIYLLPHILVYVLLGCNQEDQQEVYAEIMAVLKHDD
  QHTINTQDIASDLCQLSTQTVFSMLDHLTQWARHKFQALKAEKCPHSKSNRNKVDSMVST
  VDYEDYQSVTRFLDLIPQDTLAVASFRSKAYTRAVMHFESFITEKKQNIQEHLGFLQKLY
  AAMHEPDGVAGVSAIRKAEPSLKEQILEHESLGLLRDATACYDRAIQLEPDQIIHYHGVV
  KSMLGLGQLSTVITQVNGVHANRSEWTDELNTYRVEAAWKLSQWDLVENYLAADGKSTTW
  SVRLGQLLLSAKKRDITAFYDSLKLVRAEQIVPLSAASFERGSYQRGYEYIVRLHMLCEL
  EHSIKPLFQHSPGDSSQEDSLNWVARLEMTQNSYRAKEPILALRRALLSLNKRPDYNEMV
  GECWLQSARVARKAGHHQTAYNALLNAGESRLAELYVERAKWLWSKGDVHQALIVLQKGV
  ELCFPENETPPEGKNMLIHGRAMLLVGRFMEETANFESNAIMKKYKDVTACLPEWEDGHF
  YLAKYYDKLMPMVTDNKMEKQGDLIRYIVLHFGRSLQYGNQFIYQSMPRMLTLWLDYGTK
  AYEWEKAGRSDRVQMRNDLGKINKVITEHTNYLAPYQFLTAFSQLISRICHSHDEVFVVL
  MEIIAKVFLAYPQQAMWMMTAVSKSSYPMRVNRCKEILNKAIHMKKSLEKFVGDATRLTD
  KLLELCNKPVDGSSSTLSMSTHFKMLKKLVEEATFSEILIPLQSVMIPTLPSILGTHANH
  ASHEPFPGHWAYIAGFDDMVEILASLQKPKKISLKGSDGKFYIMMCKPKDDLRKDCRLME
  FNSLINKCLRKDAESRRRELHIRTYAVIPLNDECGIIEWVNNTAGLRPILTKLYKEKGVY
  MTGKELRQCMLPKSAALSEKLKVFREFLLPRHPPIFHEWFLRTFPDPTSWYSSRSAYCRS
  TAVMSMVGYILGLGDRHGENILFDSLTGECVHVDFNCLFNKGETFEVPEIVPFRLTHNMV
  NGMGPMGTEGLFRRACEVTMRLMRDQREPLMSVLKTFLHDPLVEWSKPVKGHSKAPLNET
  GEVVNEKAKTHVLDIEQRLQGVIKTRNRVTGLPLSIEGHVHYLIQEATDENLLCQMYLGW
  TPYM
• Function: Serine/threonine protein kinase which activates checkpoint signaling upon genotoxic stresses such as ionizing radiation (IR), ultraviolet light (UV), or DNA replication stalling, thereby acting as a DNA damage sensor. Recognizes the substrate consensus sequence [ST]-Q. Phosphorylates BRCA1, CHEK1, MCM2, RAD17, RPA2, SMC1 and p53/TP53, which collectively inhibit DNA replication and mitosis and promote DNA repair, recombination and apoptosis. Phosphorylates 'Ser-139' of histone variant H2AX at sites of DNA damage, thereby regulating DNA damage response mechanism. Required for FANCD2 ubiquitination. Critical for maintenance of fragile site stability and efficient regulation of centrosome duplication. Acts as a regulator of the S-G2 transition by restricting the activity of CDK1 during S-phase to prevent premature entry into G2. Acts as a regulator of the nuclear envelope integrity in response to DNA damage and stress. Acts as a mechanical stress sensor at the nuclear envelope: relocalizes to the nuclear envelope in response to mechanical stress and mediates a checkpoint via phosphorylation of CHEK1. Also promotes nuclear envelope rupture in response to DNA damage by mediating phosphorylation of LMNA at 'Ser-282', leading to lamin disassembly. Involved in the inflammatory response to genome instability and double-stranded DNA breaks: acts by localizing to micronuclei arising from genome instability and catalyzing phosphorylation of LMNA at 'Ser-395', priming LMNA for subsequent phosphorylation by CDK1 and micronuclei envelope rupture. The rupture of micronuclear envelope triggers the cGAS-STING pathway thereby activating the type I interferon response and innate immunity. Positively regulates the restart of stalled replication forks following activation by the KHDC3L-OOEP scaffold complex.
• Tissue Specificity: Ubiquitous, with highest expression in testis.; [Isoform 2]: Isoform 2 is found in pancreas, placenta and liver but not in heart, testis and ovary.
• KEGG Pathway:
  Fanconi anemia pathway (hsa03460)
  Cell cycle (hsa04110)
  p53 sig.ling pathway (hsa04115)
  Cellular senescence (hsa04218)
  Human papillomavirus infection (hsa05165)
  Human T-cell leukemia virus 1 infection (hsa05166)
  Human immunodeficiency virus 1 infection (hsa05170)
• Reactome Pathway:
  Activation of ATR in response to replication stress (R-HSA-176187)
  Regulation of HSF1-mediated heat shock response (R-HSA-3371453)
  HDR through Single Strand Annealing (SSA) (R-HSA-5685938)
  Processing of DNA double-strand break ends (R-HSA-5693607)
  Presynaptic phase of homologous DNA pairing and strand exchange (R-HSA-5693616)
  Fanconi Anemia Pathway (R-HSA-6783310)
  TP53 Regulates Transcription of DNA Repair Genes (R-HSA-6796648)
  Regulation of TP53 Activity through Phosphorylation (R-HSA-6804756)
  G2/M DNA damage checkpoint (R-HSA-69473)
  Impaired BRCA2 binding to RAD51 (R-HSA-9709570)
  Meiotic synapsis (R-HSA-1221632)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Seckel syndrome 1	DISLNT6G	Definitive	Autosomal recessive	[1]
Familial cutaneous telangiectasia and oropharyngeal predisposition cancer syndrome	DISJ57T4	Moderate	Autosomal dominant	[2]
Sarcoma	DISZDG3U	Moderate	Autosomal dominant	[3]
Seckel syndrome	DISEVUBA	Supportive	Autosomal recessive	[4]

This DOT Affected the Drug Response of 4 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Floxuridine	DM04LR2	Approved	Serine/threonine-protein kinase ATR (ATR) decreases the response to substance of Floxuridine.	[32]
Camptothecin	DM6CHNJ	Phase 3	Serine/threonine-protein kinase ATR (ATR) decreases the response to substance of Camptothecin.	[33]
Afimoxifene	DMFORDT	Phase 2	Serine/threonine-protein kinase ATR (ATR) decreases the response to substance of Afimoxifene.	[34]
LMP400	DM4FW2E	Phase 1	Serine/threonine-protein kinase ATR (ATR) decreases the response to substance of LMP400.	[33]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Serine/threonine-protein kinase ATR (ATR).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Serine/threonine-protein kinase ATR (ATR).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Serine/threonine-protein kinase ATR (ATR).	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Serine/threonine-protein kinase ATR (ATR).	[8]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Serine/threonine-protein kinase ATR (ATR).	[9]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Serine/threonine-protein kinase ATR (ATR).	[11]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Serine/threonine-protein kinase ATR (ATR).	[12]
Decitabine	DMQL8XJ	Approved	Decitabine increases the activity of Serine/threonine-protein kinase ATR (ATR).	[13]
Aspirin	DM672AH	Approved	Aspirin decreases the expression of Serine/threonine-protein kinase ATR (ATR).	[14]
Acetic Acid, Glacial	DM4SJ5Y	Approved	Acetic Acid, Glacial decreases the expression of Serine/threonine-protein kinase ATR (ATR).	[16]
Motexafin gadolinium	DMEJKRF	Approved	Motexafin gadolinium decreases the expression of Serine/threonine-protein kinase ATR (ATR).	[16]
Nefazodone	DM4ZS8M	Approved	Nefazodone decreases the expression of Serine/threonine-protein kinase ATR (ATR).	[17]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Serine/threonine-protein kinase ATR (ATR).	[18]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of Serine/threonine-protein kinase ATR (ATR).	[21]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate increases the expression of Serine/threonine-protein kinase ATR (ATR).	[9]
GALLICACID	DM6Y3A0	Investigative	GALLICACID decreases the expression of Serine/threonine-protein kinase ATR (ATR).	[22]
[3H]methyltrienolone	DMTSGOW	Investigative	[3H]methyltrienolone increases the expression of Serine/threonine-protein kinase ATR (ATR).	[23]
4-hydroxy-2-nonenal	DM2LJFZ	Investigative	4-hydroxy-2-nonenal decreases the expression of Serine/threonine-protein kinase ATR (ATR).	[24]
2-AMINO-1-METHYL-6-PHENYLIMIDAZO[4,5-B]PYRIDINE	DMNQL17	Investigative	2-AMINO-1-METHYL-6-PHENYLIMIDAZO[4,5-B]PYRIDINE affects the expression of Serine/threonine-protein kinase ATR (ATR).	[25]
U0126	DM31OGF	Investigative	U0126 decreases the activity of Serine/threonine-protein kinase ATR (ATR).	[27]
OXYBENZONE	DMMZYX6	Investigative	OXYBENZONE increases the expression of Serine/threonine-protein kinase ATR (ATR).	[28]
CYANATE	DM6HQDL	Investigative	CYANATE increases the expression of Serine/threonine-protein kinase ATR (ATR).	[30]
NU-6027	DMELYAX	Investigative	NU-6027 decreases the activity of Serine/threonine-protein kinase ATR (ATR).	[31]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Serine/threonine-protein kinase ATR (ATR).	[10]
Acocantherin	DM7JT24	Approved	Acocantherin decreases the phosphorylation of Serine/threonine-protein kinase ATR (ATR).	[15]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Serine/threonine-protein kinase ATR (ATR).	[19]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Serine/threonine-protein kinase ATR (ATR).	[20]
acrolein	DMAMCSR	Investigative	acrolein increases the phosphorylation of Serine/threonine-protein kinase ATR (ATR).	[26]
ABBV-744	DMTEA9C	Investigative	ABBV-744 increases the phosphorylation of Serine/threonine-protein kinase ATR (ATR).	[29]

References

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• [4] A splicing mutation affecting expression of ataxia-telangiectasia and Rad3-related protein (ATR) results in Seckel syndrome. Nat Genet. 2003 Apr;33(4):497-501. doi: 10.1038/ng1129. Epub 2003 Mar 17.
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• [11] 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.
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• [13] An ATM- and Rad3-related (ATR) signaling pathway and a phosphorylation-acetylation cascade are involved in activation of p53/p21Waf1/Cip1 in response to 5-aza-2'-deoxycytidine treatment. J Biol Chem. 2008 Feb 1;283(5):2564-74. doi: 10.1074/jbc.M702454200. Epub 2007 Oct 31.
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• [16] Motexafin gadolinium and zinc induce oxidative stress responses and apoptosis in B-cell lymphoma lines. Cancer Res. 2005 Dec 15;65(24):11676-88.
• [17] Involvement of mitochondrial dysfunction in nefazodone-induced hepatotoxicity. Food Chem Toxicol. 2016 Aug;94:148-58. doi: 10.1016/j.fct.2016.06.001. Epub 2016 Jun 8.
• [18] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [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] 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.
• [21] Induction of DNA damage by deguelin is mediated through reducing DNA repair genes in human non-small cell lung cancer NCI-H460 cells. Oncol Rep. 2012 Apr;27(4):959-64. doi: 10.3892/or.2012.1622. Epub 2012 Jan 4.
• [22] Gallic acid provokes DNA damage and suppresses DNA repair gene expression in human prostate cancer PC-3 cells. Environ Toxicol. 2013 Oct;28(10):579-87. doi: 10.1002/tox.20752. Epub 2011 Sep 2.
• [23] Genome-wide impact of androgen receptor trapped clone-27 loss on androgen-regulated transcription in prostate cancer cells. Cancer Res. 2009 Apr 1;69(7):3140-7. doi: 10.1158/0008-5472.CAN-08-3738. Epub 2009 Mar 24.
• [24] Microarray analysis of H2O2-, HNE-, or tBH-treated ARPE-19 cells. Free Radic Biol Med. 2002 Nov 15;33(10):1419-32.
• [25] Ex vivo/in vitro protective effect of myricetin bulk and nano-forms on PhIP-induced DNA damage in lymphocytes from healthy individuals and pre-cancerous MGUS patients. Arch Toxicol. 2020 Jul;94(7):2349-2357. doi: 10.1007/s00204-020-02754-x. Epub 2020 Apr 27.
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• [31] Identification and evaluation of a potent novel ATR inhibitor, NU6027, in breast and ovarian cancer cell lines. Br J Cancer. 2011 Jul 26;105(3):372-81. doi: 10.1038/bjc.2011.243. Epub 2011 Jul 5.
• [32] Poly(ADP-Ribose) polymerase inhibition synergizes with 5-fluorodeoxyuridine but not 5-fluorouracil in ovarian cancer cells. Cancer Res. 2011 Jul 15;71(14):4944-54. doi: 10.1158/0008-5472.CAN-11-0814. Epub 2011 May 25.
• [33] ATR inhibitors VE-821 and VX-970 sensitize cancer cells to topoisomerase i inhibitors by disabling DNA replication initiation and fork elongation responses. Cancer Res. 2014 Dec 1;74(23):6968-79.
• [34] High-throughput ectopic expression screen for tamoxifen resistance identifies an atypical kinase that blocks autophagy. Proc Natl Acad Sci U S A. 2011 Feb 1;108(5):2058-63.