Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTHWU8IJ)

• DOT Name: Origin recognition complex subunit 1 (ORC1)
• Synonyms: Replication control protein 1
• Gene Name: ORC1
• Related Disease:
  Hepatocellular carcinoma
  Meier-Gorlin syndrome 1
  Neoplasm
  Fetal growth restriction
  Isolated growth hormone deficiency type IA
  Myeloproliferative neoplasm
  Ornithine translocase deficiency
  Seckel syndrome
  Isolated congenital microcephaly
  Meier-Gorlin syndrome
  Microlissencephaly
  Malaria
• UniProt ID: ORC1_HUMAN
• PDB ID: 5UJ7; 5UJM; 6P3W; 7CTF; 7CTG; 7JPO; 7JPP; 7JPR; 7JPS
• Pfam ID: PF00004 ; PF17872 ; PF01426 ; PF09079
• Sequence:
  MAHYPTRLKTRKTYSWVGRPLLDRKLHYQTYREMCVKTEGCSTEIHIQIGQFVLIEGDDD
  ENPYVAKLLELFEDDSDPPPKKRARVQWFVRFCEVPACKRHLLGRKPGAQEIFWYDYPAC
  DSNINAETIIGLVRVIPLAPKDVVPTNLKNEKTLFVKLSWNEKKFRPLSSELFAELNKPQ
  ESAAKCQKPVRAKSKSAESPSWTPAEHVAKRIESRHSASKSRQTPTHPLTPRARKRLELG
  NLGNPQMSQQTSCASLDSPGRIKRKVAFSEITSPSKRSQPDKLQTLSPALKAPEKTRETG
  LSYTEDDKKASPEHRIILRTRIAASKTIDIREERTLTPISGGQRSSVVPSVILKPENIKK
  RDAKEAKAQNEATSTPHRIRRKSSVLTMNRIRQQLRFLGNSKSDQEEKEILPAAEISDSS
  SDEEEASTPPLPRRAPRTVSRNLRSSLKSSLHTLTKVPKKSLKPRTPRCAAPQIRSRSLA
  AQEPASVLEEARLRLHVSAVPESLPCREQEFQDIYNFVESKLLDHTGGCMYISGVPGTGK
  TATVHEVIRCLQQAAQANDVPPFQYIEVNGMKLTEPHQVYVQILQKLTGQKATANHAAEL
  LAKQFCTRGSPQETTVLLVDELDLLWTHKQDIMYNLFDWPTHKEARLVVLAIANTMDLPE
  RIMMNRVSSRLGLTRMCFQPYTYSQLQQILRSRLKHLKAFEDDAIQLVARKVAALSGDAR
  RCLDICRRATEICEFSQQKPDSPGLVTIAHSMEAVDEMFSSSYITAIKNSSVLEQSFLRA
  ILAEFRRSGLEEATFQQIYSQHVALCRMEGLPYPTMSETMAVCSHLGSCRLLLVEPSRND
  LLLRVRLNVSQDDVLYALKDE
• Function: Component of the origin recognition complex (ORC) that binds origins of replication. DNA-binding is ATP-dependent. The 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.
• 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)
  G1/S-Specific Transcription (R-HSA-69205)
  E2F-enabled inhibition of pre-replication complex formation (R-HSA-113507)

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hepatocellular carcinoma	DIS0J828	Definitive	Biomarker	[1]
Meier-Gorlin syndrome 1	DIS0AMX8	Definitive	Autosomal recessive	[2]
Neoplasm	DISZKGEW	Definitive	Biomarker	[3]
Fetal growth restriction	DIS5WEJ5	Strong	Biomarker	[2]
Isolated growth hormone deficiency type IA	DISLPIAM	Strong	Biomarker	[4]
Myeloproliferative neoplasm	DIS5KAPA	Strong	Biomarker	[2]
Ornithine translocase deficiency	DISITN7S	Strong	Genetic Variation	[5]
Seckel syndrome	DISEVUBA	Strong	Genetic Variation	[2]
Isolated congenital microcephaly	DISUXHZ6	moderate	Genetic Variation	[6]
Meier-Gorlin syndrome	DISCFIU3	Supportive	Autosomal dominant	[7]
Microlissencephaly	DISUCKNT	Disputed	Biomarker	[2]
Malaria	DISQ9Y50	Limited	Genetic Variation	[8]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Irinotecan	DMP6SC2	Approved	Origin recognition complex subunit 1 (ORC1) increases the response to substance of Irinotecan.	[33]

24 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 1 (ORC1).	[9]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Origin recognition complex subunit 1 (ORC1).	[10]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Origin recognition complex subunit 1 (ORC1).	[11]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Origin recognition complex subunit 1 (ORC1).	[12]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Origin recognition complex subunit 1 (ORC1).	[13]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Origin recognition complex subunit 1 (ORC1).	[14]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Origin recognition complex subunit 1 (ORC1).	[14]
Demecolcine	DMCZQGK	Approved	Demecolcine decreases the expression of Origin recognition complex subunit 1 (ORC1).	[15]
Niclosamide	DMJAGXQ	Approved	Niclosamide decreases the expression of Origin recognition complex subunit 1 (ORC1).	[1]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the expression of Origin recognition complex subunit 1 (ORC1).	[17]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of Origin recognition complex subunit 1 (ORC1).	[18]
Azathioprine	DMMZSXQ	Approved	Azathioprine decreases the expression of Origin recognition complex subunit 1 (ORC1).	[19]
Dasatinib	DMJV2EK	Approved	Dasatinib decreases the expression of Origin recognition complex subunit 1 (ORC1).	[20]
Methamphetamine	DMPM4SK	Approved	Methamphetamine decreases the expression of Origin recognition complex subunit 1 (ORC1).	[21]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Origin recognition complex subunit 1 (ORC1).	[22]
Chlorpromazine	DMBGZI3	Phase 3 Trial	Chlorpromazine decreases the expression of Origin recognition complex subunit 1 (ORC1).	[23]
GSK2110183	DMZHB37	Phase 2	GSK2110183 decreases the expression of Origin recognition complex subunit 1 (ORC1).	[24]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Origin recognition complex subunit 1 (ORC1).	[25]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Origin recognition complex subunit 1 (ORC1).	[26]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Origin recognition complex subunit 1 (ORC1).	[28]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Origin recognition complex subunit 1 (ORC1).	[30]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Origin recognition complex subunit 1 (ORC1).	[12]
Glyphosate	DM0AFY7	Investigative	Glyphosate decreases the expression of Origin recognition complex subunit 1 (ORC1).	[31]
GW-3965	DMG60ET	Investigative	GW-3965 decreases the expression of Origin recognition complex subunit 1 (ORC1).	[32]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Origin recognition complex subunit 1 (ORC1).	[27]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Origin recognition complex subunit 1 (ORC1).	[29]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Origin recognition complex subunit 1 (ORC1).	[29]

References

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• [3] Diminished origin-licensing capacity specifically sensitizes tumor cells to replication stress.Mol Cancer Res. 2013 Apr;11(4):370-80. doi: 10.1158/1541-7786.MCR-12-0491. Epub 2013 Jan 30.
• [4] The BAH domain of ORC1 links H4K20me2 to DNA replication licensing and Meier-Gorlin syndrome.Nature. 2012 Mar 7;484(7392):115-9. doi: 10.1038/nature10956.
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• [18] Effects of ciglitazone and troglitazone on the proliferation of human stomach cancer cells. World J Gastroenterol. 2009 Jan 21;15(3):310-20.
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• [21] Methamphetamine alters the normal progression by inducing cell cycle arrest in astrocytes. PLoS One. 2014 Oct 7;9(10):e109603.
• [22] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
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• [33] Gene expression analysis using human cancer xenografts to identify novel predictive marker genes for the efficacy of 5-fluorouracil-based drugs. Cancer Sci. 2006 Jun;97(6):510-22. doi: 10.1111/j.1349-7006.2006.00204.x.