Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT19PNNG)

• DOT Name: DNA replication licensing factor MCM4 (MCM4)
• Synonyms: EC 3.6.4.12; CDC21 homolog; P1-CDC21
• Gene Name: MCM4
• Related Disease:
  Aarskog-Scott syndrome, X-linked
  Adrenocortical insufficiency
  Cervical cancer
  Cervical carcinoma
  Colorectal carcinoma
  Esophageal squamous cell carcinoma
  Fanconi's anemia
  Hepatocellular carcinoma
  Medulloblastoma
  Neoplasm
  Non-small-cell lung cancer
  Primary immunodeficiency with natural-killer cell deficiency and adrenal insufficiency
  Skin cancer
  Clear cell renal carcinoma
  Laryngeal squamous cell carcinoma
  Lung adenocarcinoma
  Meningioma
  Nasopharyngeal carcinoma
  Renal cell carcinoma
  X-linked adrenal hypoplasia congenita
  Cutaneous melanoma
  Squamous cell carcinoma
• UniProt ID: MCM4_HUMAN
• PDB ID: 6XTX; 6XTY; 7PFO; 7PLO; 7W1Y; 7W68; 8B9D
• EC Number: 3.6.4.12
• Pfam ID: PF00493 ; PF21128 ; PF17855 ; PF14551 ; PF17207
• Sequence:
  MSSPASTPSRRGSRRGRATPAQTPRSEDARSSPSQRRRGEDSTSTGELQPMPTSPGVDLQ
  SPAAQDVLFSSPPQMHSSAIPLDFDVSSPLTYGTPSSRVEGTPRSGVRGTPVRQRPDLGS
  AQKGLQVDLQSDGAAAEDIVASEQSLGQKLVIWGTDVNVAACKENFQRFLQRFIDPLAKE
  EENVGIDITEPLYMQRLGEINVIGEPFLNVNCEHIKSFDKNLYRQLISYPQEVIPTFDMA
  VNEIFFDRYPDSILEHQIQVRPFNALKTKNMRNLNPEDIDQLITISGMVIRTSQLIPEMQ
  EAFFQCQVCAHTTRVEMDRGRIAEPSVCGRCHTTHSMALIHNRSLFSDKQMIKLQESPED
  MPAGQTPHTVILFAHNDLVDKVQPGDRVNVTGIYRAVPIRVNPRVSNVKSVYKTHIDVIH
  YRKTDAKRLHGLDEEAEQKLFSEKRVELLKELSRKPDIYERLASALAPSIYEHEDIKKGI
  LLQLFGGTRKDFSHTGRGKFRAEINILLCGDPGTSKSQLLQYVYNLVPRGQYTSGKGSSA
  VGLTAYVMKDPETRQLVLQTGALVLSDNGICCIDEFDKMNESTRSVLHEVMEQQTLSIAK
  AGIICQLNARTSVLAAANPIESQWNPKKTTIENIQLPHTLLSRFDLIFLLLDPQDEAYDR
  RLAHHLVALYYQSEEQAEEELLDMAVLKDYIAYAHSTIMPRLSEEASQALIEAYVDMRKI
  GSSRGMVSAYPRQLESLIRLAEAHAKVRLSNKVEAIDVEEAKRLHREALKQSATDPRTGI
  VDISILTTGMSATSRKRKEELAEALKKLILSKGKTPALKYQQLFEDIRGQSDIAITKDMF
  EEALRALADDDFLTVTGKTVRLL
• Function: Acts as a component of the MCM2-7 complex (MCM complex) which is the replicative helicase essential for 'once per cell cycle' DNA replication initiation and elongation in eukaryotic cells. Core component of CDC45-MCM-GINS (CMG) helicase, the molecular machine that unwinds template DNA during replication, and around which the replisome is built. The active ATPase sites in the MCM2-7 ring are formed through the interaction surfaces of two neighboring subunits such that a critical structure of a conserved arginine finger motif is provided in trans relative to the ATP-binding site of the Walker A box of the adjacent subunit. The six ATPase active sites, however, are likely to contribute differentially to the complex helicase activity.
• KEGG Pathway:
  D. replication (hsa03030)
  Cell cycle (hsa04110)
• Reactome Pathway:
  Unwinding of DNA (R-HSA-176974)
  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)
  Switching of origins to a post-replicative state (R-HSA-69052)
  Activation of ATR in response to replication stress (R-HSA-176187)

Molecular Interaction Atlas (MIA) of This DOT

22 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Aarskog-Scott syndrome, X-linked	DISNHV62	Strong	Biomarker	[1]
Adrenocortical insufficiency	DISZ0CPT	Strong	Biomarker	[2]
Cervical cancer	DISFSHPF	Strong	Biomarker	[3]
Cervical carcinoma	DIST4S00	Strong	Biomarker	[3]
Colorectal carcinoma	DIS5PYL0	Strong	Genetic Variation	[4]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Biomarker	[5]
Fanconi's anemia	DISGW6Q8	Strong	Biomarker	[6]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[7]
Medulloblastoma	DISZD2ZL	Strong	Altered Expression	[8]
Neoplasm	DISZKGEW	Strong	Altered Expression	[9]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[10]
Primary immunodeficiency with natural-killer cell deficiency and adrenal insufficiency	DIS7ZIZF	Strong	Autosomal recessive	[11]
Skin cancer	DISTM18U	Strong	Genetic Variation	[12]
Clear cell renal carcinoma	DISBXRFJ	moderate	Altered Expression	[13]
Laryngeal squamous cell carcinoma	DIS9UUVF	moderate	Biomarker	[14]
Lung adenocarcinoma	DISD51WR	moderate	Biomarker	[15]
Meningioma	DISPT4TG	moderate	Biomarker	[16]
Nasopharyngeal carcinoma	DISAOTQ0	moderate	Biomarker	[17]
Renal cell carcinoma	DISQZ2X8	moderate	Altered Expression	[13]
X-linked adrenal hypoplasia congenita	DISNMXY8	moderate	Biomarker	[18]
Cutaneous melanoma	DIS3MMH9	Limited	Altered Expression	[19]
Squamous cell carcinoma	DISQVIFL	Limited	Biomarker	[20]

40 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 DNA replication licensing factor MCM4 (MCM4).	[21]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of DNA replication licensing factor MCM4 (MCM4).	[22]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of DNA replication licensing factor MCM4 (MCM4).	[23]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of DNA replication licensing factor MCM4 (MCM4).	[24]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of DNA replication licensing factor MCM4 (MCM4).	[25]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of DNA replication licensing factor MCM4 (MCM4).	[26]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of DNA replication licensing factor MCM4 (MCM4).	[27]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of DNA replication licensing factor MCM4 (MCM4).	[28]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of DNA replication licensing factor MCM4 (MCM4).	[29]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the expression of DNA replication licensing factor MCM4 (MCM4).	[30]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of DNA replication licensing factor MCM4 (MCM4).	[31]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of DNA replication licensing factor MCM4 (MCM4).	[31]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of DNA replication licensing factor MCM4 (MCM4).	[33]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil affects the expression of DNA replication licensing factor MCM4 (MCM4).	[34]
Demecolcine	DMCZQGK	Approved	Demecolcine decreases the expression of DNA replication licensing factor MCM4 (MCM4).	[35]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the expression of DNA replication licensing factor MCM4 (MCM4).	[36]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of DNA replication licensing factor MCM4 (MCM4).	[37]
Azathioprine	DMMZSXQ	Approved	Azathioprine decreases the expression of DNA replication licensing factor MCM4 (MCM4).	[38]
Irinotecan	DMP6SC2	Approved	Irinotecan decreases the expression of DNA replication licensing factor MCM4 (MCM4).	[39]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of DNA replication licensing factor MCM4 (MCM4).	[40]
Simvastatin	DM30SGU	Approved	Simvastatin decreases the expression of DNA replication licensing factor MCM4 (MCM4).	[41]
Atropine	DMEN6X7	Approved	Atropine increases the expression of DNA replication licensing factor MCM4 (MCM4).	[42]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of DNA replication licensing factor MCM4 (MCM4).	[43]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of DNA replication licensing factor MCM4 (MCM4).	[44]
GSK2110183	DMZHB37	Phase 2	GSK2110183 decreases the expression of DNA replication licensing factor MCM4 (MCM4).	[45]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of DNA replication licensing factor MCM4 (MCM4).	[46]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of DNA replication licensing factor MCM4 (MCM4).	[47]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of DNA replication licensing factor MCM4 (MCM4).	[49]
Geldanamycin	DMS7TC5	Discontinued in Phase 2	Geldanamycin increases the expression of DNA replication licensing factor MCM4 (MCM4).	[51]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of DNA replication licensing factor MCM4 (MCM4).	[52]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of DNA replication licensing factor MCM4 (MCM4).	[53]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of DNA replication licensing factor MCM4 (MCM4).	[54]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of DNA replication licensing factor MCM4 (MCM4).	[35]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of DNA replication licensing factor MCM4 (MCM4).	[55]
Glyphosate	DM0AFY7	Investigative	Glyphosate decreases the expression of DNA replication licensing factor MCM4 (MCM4).	[56]
Nickel chloride	DMI12Y8	Investigative	Nickel chloride decreases the expression of DNA replication licensing factor MCM4 (MCM4).	[57]
4-hydroxy-2-nonenal	DM2LJFZ	Investigative	4-hydroxy-2-nonenal decreases the expression of DNA replication licensing factor MCM4 (MCM4).	[30]
Lithium chloride	DMHYLQ2	Investigative	Lithium chloride decreases the expression of DNA replication licensing factor MCM4 (MCM4).	[58]
Manganese	DMKT129	Investigative	Manganese decreases the expression of DNA replication licensing factor MCM4 (MCM4).	[59]
GW-3965	DMG60ET	Investigative	GW-3965 decreases the expression of DNA replication licensing factor MCM4 (MCM4).	[60]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Decitabine	DMQL8XJ	Approved	Decitabine affects the methylation of DNA replication licensing factor MCM4 (MCM4).	[32]
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of DNA replication licensing factor MCM4 (MCM4).	[48]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of DNA replication licensing factor MCM4 (MCM4).	[50]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of DNA replication licensing factor MCM4 (MCM4).	[50]

References

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