Details of Drug Off-Target (DOT)

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

• DOT Name: Eukaryotic translation initiation factor 4E (EIF4E)
• Synonyms: eIF-4E; eIF4E; eIF-4F 25 kDa subunit; mRNA cap-binding protein
• Gene Name: EIF4E
• Related Disease: Autism, susceptibility to, 19
• UniProt ID: IF4E_HUMAN
• PDB ID: 1IPB ; 1IPC ; 1WKW ; 2GPQ ; 2V8W ; 2V8X ; 2V8Y ; 2W97 ; 3AM7 ; 3TF2 ; 3U7X ; 4AZA ; 4BEA ; 4DT6 ; 4DUM ; 4TPW ; 4TQB ; 4TQC ; 4UED ; 5EHC ; 5EI3 ; 5EIR ; 5EKV ; 5GW6 ; 5T46 ; 5ZJY ; 5ZJZ ; 5ZK5 ; 5ZK7 ; 5ZK9 ; 5ZML ; 7D6Y ; 7D8B ; 7EZW ; 7F07 ; 7MEU ; 7XTP ; 8SX4
• Pfam ID: PF01652
• Sequence:
  MATVEPETTPTPNPPTTEEEKTESNQEVANPEHYIKHPLQNRWALWFFKNDKSKTWQANL
  RLISKFDTVEDFWALYNHIQLSSNLMPGCDYSLFKDGIEPMWEDEKNKRGGRWLITLNKQ
  QRRSDLDRFWLETLLCLIGESFDDYSDDVCGAVVNVRAKGDKIAIWTTECENREAVTHIG
  RVYKERLGLPPKIVIGYQSHADTATKSGSTTKNRFVV
• Function: Acts in the cytoplasm to initiate and regulate protein synthesis and is required in the nucleus for export of a subset of mRNAs from the nucleus to the cytoplasm which promotes processes such as RNA capping, processing and splicing. Component of the protein complex eIF4F, which is involved in the recognition of the mRNA cap, ATP-dependent unwinding of 5'-terminal secondary structure and recruitment of mRNA to the ribosome. This protein recognizes and binds the 7-methylguanosine (m7G)-containing mRNA cap during an early step in the initiation of protein synthesis and facilitates ribosome binding by inducing the unwinding of the mRNAs secondary structures. Together with EIF4G1, antagonizes the scanning promoted by EIF1-EIF4G1 and is required for TISU translation, a process where the TISU element recognition makes scanning unnecessary. In addition to its role in translation initiation, also acts as a regulator of translation and stability in the cytoplasm. Component of the CYFIP1-EIF4E-FMR1 complex which binds to the mRNA cap and mediates translational repression: in the complex, EIF4E mediates the binding to the mRNA cap. Component of a multiprotein complex that sequesters and represses translation of proneurogenic factors during neurogenesis. In P-bodies, component of a complex that mediates the storage of translationally inactive mRNAs in the cytoplasm and prevents their degradation. May play an important role in spermatogenesis through translational regulation of stage-specific mRNAs during germ cell development. As well as its roles in translation, also involved in mRNA nucleocytoplasmic transport. Its role in mRNA export from the nucleus to the cytoplasm relies on its ability to bind the m7G cap of RNAs and on the presence of the 50-nucleotide EIF4E sensitivity element (4ESE) in the 3'UTR of sensitive transcripts. Interaction with the 4ESE is mediated by LRPPRC which binds simultaneously to both EIF4E and the 4ESE, thereby acting as a platform for assembly for the RNA export complex. EIF4E-dependent mRNA export is independent of ongoing protein or RNA synthesis and is also NFX1-independent but is XPO1-dependent with LRPPRC interacting with XPO1 to form an EIF4E-dependent mRNA export complex. Alters the composition of the cytoplasmic face of the nuclear pore to promote RNA export by reducing RANBP2 expression, relocalizing nucleoporin NUP214 and increasing expression of RANBP1 and RNA export factors DDX19 and GLE1. Promotes the nuclear export of cyclin CCND1 mRNA. Promotes the nuclear export of NOS2/iNOS mRNA. Promotes the nuclear export of MDM2 mRNA. Promotes the export of additional mRNAs, including others involved in the cell cycle. In the nucleus, binds to capped splice factor-encoding mRNAs and stimulates their nuclear export to enhance splice factor production by increasing their cytoplasmic availability to the translation machinery. May also regulate splicing through interaction with the spliceosome in an RNA and m7G cap-dependent manner. Also binds to some pre-mRNAs and may play a role in their recruitment to the spliceosome. Promotes steady-state capping of a subset of coding and non-coding RNAs by mediating nuclear export of capping machinery mRNAs including RNMT, RNGTT and RAMAC to enhance their translation. Stimulates mRNA 3'-end processing by promoting the expression of several core cleavage complex factors required for mRNA cleavage and polyadenylation, and may also have a direct effect through its interaction with the CPSF3 cleavage enzyme. Rescues cells from apoptosis by promoting activation of serine/threonine-protein kinase AKT1 through mRNA export of NBS1 which potentiates AKT1 phosphorylation and also through mRNA export of AKT1 effectors, allowing for increased production of these proteins.
• KEGG Pathway:
  EGFR tyrosine ki.se inhibitor resistance (hsa01521)
  HIF-1 sig.ling pathway (hsa04066)
  mTOR sig.ling pathway (hsa04150)
  PI3K-Akt sig.ling pathway (hsa04151)
  Longevity regulating pathway (hsa04211)
  Insulin sig.ling pathway (hsa04910)
• Reactome Pathway:
  L13a-mediated translational silencing of Ceruloplasmin expression (R-HSA-156827)
  Transport of the SLBP independent Mature mRNA (R-HSA-159227)
  Transport of the SLBP Dependant Mature mRNA (R-HSA-159230)
  Transport of Mature mRNA Derived from an Intronless Transcript (R-HSA-159231)
  mTORC1-mediated signalling (R-HSA-166208)
  Deadenylation of mRNA (R-HSA-429947)
  Translation initiation complex formation (R-HSA-72649)
  Activation of the mRNA upon binding of the cap-binding complex and eIFs, and subsequent binding to 43S (R-HSA-72662)
  Ribosomal scanning and start codon recognition (R-HSA-72702)
  GTP hydrolysis and joining of the 60S ribosomal subunit (R-HSA-72706)
  M-decay (R-HSA-9820841)
  Z-decay (R-HSA-9820865)
  ISG15 antiviral mechanism (R-HSA-1169408)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autism, susceptibility to, 19	DIS4CNXL	Limited	Unknown	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ethanol	DMDRQZU	Approved	Eukaryotic translation initiation factor 4E (EIF4E) increases the Blood insulin abnormal ADR of Ethanol.	[34]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Eukaryotic translation initiation factor 4E (EIF4E).	[2]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Eukaryotic translation initiation factor 4E (EIF4E).	[3]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Eukaryotic translation initiation factor 4E (EIF4E).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Eukaryotic translation initiation factor 4E (EIF4E).	[5]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Eukaryotic translation initiation factor 4E (EIF4E).	[6]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Eukaryotic translation initiation factor 4E (EIF4E).	[7]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil increases the expression of Eukaryotic translation initiation factor 4E (EIF4E).	[9]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Eukaryotic translation initiation factor 4E (EIF4E).	[10]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of Eukaryotic translation initiation factor 4E (EIF4E).	[11]
Imatinib	DM7RJXL	Approved	Imatinib decreases the expression of Eukaryotic translation initiation factor 4E (EIF4E).	[14]
Momelotinib	DMF98Q0	Approved	Momelotinib decreases the expression of Eukaryotic translation initiation factor 4E (EIF4E).	[16]
Rigosertib	DMOSTXF	Phase 3	Rigosertib decreases the activity of Eukaryotic translation initiation factor 4E (EIF4E).	[17]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Eukaryotic translation initiation factor 4E (EIF4E).	[18]
GSK2110183	DMZHB37	Phase 2	GSK2110183 decreases the expression of Eukaryotic translation initiation factor 4E (EIF4E).	[19]
Ribavirin	DMEYLH9	Phase 1 Trial	Ribavirin decreases the expression of Eukaryotic translation initiation factor 4E (EIF4E).	[24]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Eukaryotic translation initiation factor 4E (EIF4E).	[27]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Eukaryotic translation initiation factor 4E (EIF4E).	[28]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Eukaryotic translation initiation factor 4E (EIF4E).	[29]
KOJIC ACID	DMP84CS	Investigative	KOJIC ACID decreases the expression of Eukaryotic translation initiation factor 4E (EIF4E).	[30]
Rapamycin Immunosuppressant Drug	DM678IB	Investigative	Rapamycin Immunosuppressant Drug decreases the activity of Eukaryotic translation initiation factor 4E (EIF4E).	[31]
OXYBENZONE	DMMZYX6	Investigative	OXYBENZONE increases the expression of Eukaryotic translation initiation factor 4E (EIF4E).	[32]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the phosphorylation of Eukaryotic translation initiation factor 4E (EIF4E).	[8]
Ibuprofen	DM8VCBE	Approved	Ibuprofen increases the phosphorylation of Eukaryotic translation initiation factor 4E (EIF4E).	[12]
Sorafenib	DMS8IFC	Approved	Sorafenib decreases the phosphorylation of Eukaryotic translation initiation factor 4E (EIF4E).	[13]
Orlistat	DMRJSP8	Approved	Orlistat increases the phosphorylation of Eukaryotic translation initiation factor 4E (EIF4E).	[15]
Flurbiprofen	DMGN4BY	Approved	Flurbiprofen increases the phosphorylation of Eukaryotic translation initiation factor 4E (EIF4E).	[12]
phorbol 12-myristate 13-acetate	DMJWD62	Phase 2	phorbol 12-myristate 13-acetate increases the phosphorylation of Eukaryotic translation initiation factor 4E (EIF4E).	[20]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Eukaryotic translation initiation factor 4E (EIF4E).	[21]
Mivebresib	DMCPF90	Phase 1	Mivebresib decreases the phosphorylation of Eukaryotic translation initiation factor 4E (EIF4E).	[22]
LY294002	DMY1AFS	Phase 1	LY294002 decreases the phosphorylation of Eukaryotic translation initiation factor 4E (EIF4E).	[23]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Eukaryotic translation initiation factor 4E (EIF4E).	[26]
PD98059	DMZC90M	Investigative	PD98059 decreases the phosphorylation of Eukaryotic translation initiation factor 4E (EIF4E).	[23]
Fascaplysin	DMG5OZP	Investigative	Fascaplysin decreases the phosphorylation of Eukaryotic translation initiation factor 4E (EIF4E).	[33]
CGP-57380	DMFPOUC	Investigative	CGP-57380 decreases the phosphorylation of Eukaryotic translation initiation factor 4E (EIF4E).	[20]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Guanosine	DM4T5LH	Phase 1	Guanosine affects the binding of Eukaryotic translation initiation factor 4E (EIF4E).	[25]

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