Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTKQN3KP)

• DOT Name: Origin recognition complex subunit 6 (ORC6)
• Gene Name: ORC6
• Related Disease:
  Meier-Gorlin syndrome 3
  Advanced cancer
  Colon cancer
  Colon carcinoma
  Colonic neoplasm
  Myeloproliferative neoplasm
  Seckel syndrome
  Mungan syndrome
  Meier-Gorlin syndrome
• UniProt ID: ORC6_HUMAN
• PDB ID: 3M03; 6KVG
• Pfam ID: PF05460
• Sequence:
  MGSELIGRLAPRLGLAEPDMLRKAEEYLRLSRVKCVGLSARTTETSSAVMCLDLAASWMK
  CPLDRAYLIKLSGLNKETYQSCLKSFECLLGLNSNIGIRDLAVQFSCIEAVNMASKILKS
  YESSLPQTQQVDLDLSRPLFTSAALLSACKILKLKVDKNKMVATSGVKKAIFDRLCKQLE
  KIGQQVDREPGDVATPPRKRKKIVVEAPAKEMEKVEEMPHKPQKDEDLTQDYEEWKRKIL
  ENAASAQKATAE
• Function: Component of the origin recognition complex (ORC) that binds origins of replication. DNA-binding is ATP-dependent. The specific DNA sequences that define origins of replication have not been identified yet. ORC is required to assemble the pre-replication complex necessary to initiate DNA replication. Does not bind histone H3 and H4 trimethylation marks H3K9me3, H3K27me3 and H4K20me3.
• KEGG Pathway: Cell cycle (hsa04110)
• Reactome Pathway:
  Activation of ATR in response to replication stress (R-HSA-176187)
  Assembly of the ORC complex at the origin of replication (R-HSA-68616)
  CDC6 association with the ORC (R-HSA-68689)
  Assembly of the pre-replicative complex (R-HSA-68867)
  Orc1 removal from chromatin (R-HSA-68949)
  Activation of the pre-replicative complex (R-HSA-68962)
  E2F-enabled inhibition of pre-replication complex formation (R-HSA-113507)

Molecular Interaction Atlas (MIA) of This DOT

9 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Meier-Gorlin syndrome 3	DIS5W9R0	Definitive	Autosomal recessive	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Colon cancer	DISVC52G	Strong	Altered Expression	[2]
Colon carcinoma	DISJYKUO	Strong	Altered Expression	[2]
Colonic neoplasm	DISSZ04P	Strong	Biomarker	[2]
Myeloproliferative neoplasm	DIS5KAPA	Strong	Biomarker	[3]
Seckel syndrome	DISEVUBA	Strong	Biomarker	[3]
Mungan syndrome	DISNR0AY	moderate	Genetic Variation	[4]
Meier-Gorlin syndrome	DISCFIU3	Supportive	Autosomal dominant	[5]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Origin recognition complex subunit 6 (ORC6) affects the response to substance of Doxorubicin.	[29]
Vinblastine	DM5TVS3	Approved	Origin recognition complex subunit 6 (ORC6) affects the response to substance of Vinblastine.	[29]

2 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 Origin recognition complex subunit 6 (ORC6).	[6]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Origin recognition complex subunit 6 (ORC6).	[24]

23 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 Origin recognition complex subunit 6 (ORC6).	[7]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Origin recognition complex subunit 6 (ORC6).	[8]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Origin recognition complex subunit 6 (ORC6).	[9]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Origin recognition complex subunit 6 (ORC6).	[10]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Origin recognition complex subunit 6 (ORC6).	[7]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Origin recognition complex subunit 6 (ORC6).	[11]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Origin recognition complex subunit 6 (ORC6).	[11]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil increases the expression of Origin recognition complex subunit 6 (ORC6).	[12]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the expression of Origin recognition complex subunit 6 (ORC6).	[13]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of Origin recognition complex subunit 6 (ORC6).	[14]
Azathioprine	DMMZSXQ	Approved	Azathioprine decreases the expression of Origin recognition complex subunit 6 (ORC6).	[15]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of Origin recognition complex subunit 6 (ORC6).	[16]
Dasatinib	DMJV2EK	Approved	Dasatinib decreases the expression of Origin recognition complex subunit 6 (ORC6).	[17]
Lucanthone	DMZLBUO	Approved	Lucanthone decreases the expression of Origin recognition complex subunit 6 (ORC6).	[18]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Origin recognition complex subunit 6 (ORC6).	[19]
GSK2110183	DMZHB37	Phase 2	GSK2110183 decreases the expression of Origin recognition complex subunit 6 (ORC6).	[20]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Origin recognition complex subunit 6 (ORC6).	[21]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Origin recognition complex subunit 6 (ORC6).	[22]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Origin recognition complex subunit 6 (ORC6).	[23]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Origin recognition complex subunit 6 (ORC6).	[25]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Origin recognition complex subunit 6 (ORC6).	[26]
chloropicrin	DMSGBQA	Investigative	chloropicrin increases the expression of Origin recognition complex subunit 6 (ORC6).	[27]
GW-3965	DMG60ET	Investigative	GW-3965 decreases the expression of Origin recognition complex subunit 6 (ORC6).	[28]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [2] Reduction of Orc6 expression sensitizes human colon cancer cells to 5-fluorouracil and cisplatin.PLoS One. 2008;3(12):e4054. doi: 10.1371/journal.pone.0004054. Epub 2008 Dec 29.
• [3] Mutations in the pre-replication complex cause Meier-Gorlin syndrome. Nat Genet. 2011 Feb 27;43(4):356-9. doi: 10.1038/ng.775.
• [4] Drosophila model of Meier-Gorlin syndrome based on the mutation in a conserved C-Terminal domain of Orc6.Am J Med Genet A. 2015 Nov;167A(11):2533-40. doi: 10.1002/ajmg.a.37214. Epub 2015 Jul 2.
• [5] Deficiency in origin licensing proteins impairs cilia formation: implications for the aetiology of Meier-Gorlin syndrome. PLoS Genet. 2013;9(3):e1003360. doi: 10.1371/journal.pgen.1003360. Epub 2013 Mar 14.
• [6] 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.
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• [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] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [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] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [12] Multi-level gene expression profiles affected by thymidylate synthase and 5-fluorouracil in colon cancer. BMC Genomics. 2006 Apr 3;7:68. doi: 10.1186/1471-2164-7-68.
• [13] Cannabidiol-induced transcriptomic changes and cellular senescence in human Sertoli cells. Toxicol Sci. 2023 Feb 17;191(2):227-238. doi: 10.1093/toxsci/kfac131.
• [14] Effects of ciglitazone and troglitazone on the proliferation of human stomach cancer cells. World J Gastroenterol. 2009 Jan 21;15(3):310-20.
• [15] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
• [16] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [17] Dasatinib reverses cancer-associated fibroblasts (CAFs) from primary lung carcinomas to a phenotype comparable to that of normal fibroblasts. Mol Cancer. 2010 Jun 27;9:168.
• [18] Lucanthone is a novel inhibitor of autophagy that induces cathepsin D-mediated apoptosis. J Biol Chem. 2011 Feb 25;286(8):6602-13.
• [19] 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.
• [20] Novel ATP-competitive Akt inhibitor afuresertib suppresses the proliferation of malignant pleural mesothelioma cells. Cancer Med. 2017 Nov;6(11):2646-2659. doi: 10.1002/cam4.1179. Epub 2017 Sep 27.
• [21] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [22] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [23] 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.
• [24] 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.
• [25] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [26] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [27] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
• [28] System analysis of cross-talk between nuclear receptors reveals an opposite regulation of the cell cycle by LXR and FXR in human HepaRG liver cells. PLoS One. 2019 Aug 22;14(8):e0220894. doi: 10.1371/journal.pone.0220894. eCollection 2019.
• [29] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.