Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT9G360P)

• DOT Name: Insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1)
• Synonyms: IGF2 mRNA-binding protein 1; IMP-1; IMP1; Coding region determinant-binding protein; CRD-BP; IGF-II mRNA-binding protein 1; VICKZ family member 1; Zipcode-binding protein 1; ZBP-1
• Gene Name: IGF2BP1
• Related Disease:
  Advanced cancer
  Meningioma
  Acute myelogenous leukaemia
  Adenocarcinoma
  B-cell neoplasm
  Bladder cancer
  Bone osteosarcoma
  Breast cancer
  Breast carcinoma
  Carcinoma
  Cervical cancer
  Cervical carcinoma
  Childhood acute lymphoblastic leukemia
  Clear cell renal carcinoma
  Colon cancer
  Colon carcinoma
  Epithelial ovarian cancer
  Glioma
  Hepatocellular carcinoma
  leukaemia
  Leukemia
  Lung adenocarcinoma
  Lung cancer
  Lung carcinoma
  Lung neoplasm
  Melanoma
  Metastatic malignant neoplasm
  Metastatic melanoma
  Neoplasm
  Non-small-cell lung cancer
  Osteosarcoma
  Ovarian cancer
  Ovarian neoplasm
  Prostate carcinoma
  Renal cell carcinoma
  Urinary bladder cancer
  Urinary bladder neoplasm
  Coronary heart disease
  Pancreatic cancer
  Acute lymphocytic leukaemia
  Colorectal carcinoma
  Hepatitis C virus infection
  Liver cancer
  Lymphoma
  Nasopharyngeal carcinoma
  Neuroblastoma
  Non-insulin dependent diabetes
• UniProt ID: IF2B1_HUMAN
• PDB ID: 3KRM; 6QEY
• Pfam ID: PF00013 ; PF00076
• Sequence:
  MNKLYIGNLNESVTPADLEKVFAEHKISYSGQFLVKSGYAFVDCPDEHWAMKAIETFSGK
  VELQGKRLEIEHSVPKKQRSRKIQIRNIPPQLRWEVLDSLLAQYGTVENCEQVNTESETA
  VVNVTYSNREQTRQAIMKLNGHQLENHALKVSYIPDEQIAQGPENGRRGGFGSRGQPRQG
  SPVAAGAPAKQQQVDIPLRLLVPTQYVGAIIGKEGATIRNITKQTQSKIDVHRKENAGAA
  EKAISVHSTPEGCSSACKMILEIMHKEAKDTKTADEVPLKILAHNNFVGRLIGKEGRNLK
  KVEQDTETKITISSLQDLTLYNPERTITVKGAIENCCRAEQEIMKKVREAYENDVAAMSL
  QSHLIPGLNLAAVGLFPASSSAVPPPPSSVTGAAPYSSFMQAPEQEMVQVFIPAQAVGAI
  IGKKGQHIKQLSRFASASIKIAPPETPDSKVRMVIITGPPEAQFKAQGRIYGKLKEENFF
  GPKEEVKLETHIRVPASAAGRVIGKGGKTVNELQNLTAAEVVVPRDQTPDENDQVIVKII
  GHFYASQMAQRKIRDILAQVKQQHQKGQSNQAQARRK
• Function: RNA-binding factor that recruits target transcripts to cytoplasmic protein-RNA complexes (mRNPs). This transcript 'caging' into mRNPs allows mRNA transport and transient storage. It also modulates the rate and location at which target transcripts encounter the translational apparatus and shields them from endonuclease attacks or microRNA-mediated degradation. Preferentially binds to N6-methyladenosine (m6A)-containing mRNAs and increases their stability. Plays a direct role in the transport and translation of transcripts required for axonal regeneration in adult sensory neurons. Regulates localized beta-actin/ACTB mRNA translation, a crucial process for cell polarity, cell migration and neurite outgrowth. Co-transcriptionally associates with the ACTB mRNA in the nucleus. This binding involves a conserved 54-nucleotide element in the ACTB mRNA 3'-UTR, known as the 'zipcode'. The RNP thus formed is exported to the cytoplasm, binds to a motor protein and is transported along the cytoskeleton to the cell periphery. During transport, prevents ACTB mRNA from being translated into protein. When the RNP complex reaches its destination near the plasma membrane, IGF2BP1 is phosphorylated. This releases the mRNA, allowing ribosomal 40S and 60S subunits to assemble and initiate ACTB protein synthesis. Monomeric ACTB then assembles into the subcortical actin cytoskeleton. During neuronal development, key regulator of neurite outgrowth, growth cone guidance and neuronal cell migration, presumably through the spatiotemporal fine tuning of protein synthesis, such as that of ACTB. May regulate mRNA transport to activated synapses. Binds to and stabilizes ABCB1/MDR-1 mRNA. During interstinal wound repair, interacts with and stabilizes PTGS2 transcript. PTGS2 mRNA stabilization may be crucial for colonic mucosal wound healing. Binds to the 3'-UTR of IGF2 mRNA by a mechanism of cooperative and sequential dimerization and regulates IGF2 mRNA subcellular localization and translation. Binds to MYC mRNA, in the coding region instability determinant (CRD) of the open reading frame (ORF), hence preventing MYC cleavage by endonucleases and possibly microRNA targeting to MYC-CRD. Binding to MYC mRNA is enhanced by m6A-modification of the CRD. Binds to the 3'-UTR of CD44 mRNA and stabilizes it, hence promotes cell adhesion and invadopodia formation in cancer cells. Binds to the oncofetal H19 transcript and to the neuron-specific TAU mRNA and regulates their localizations. Binds to and stabilizes BTRC/FBW1A mRNA. Binds to the adenine-rich autoregulatory sequence (ARS) located in PABPC1 mRNA and represses its translation. PABPC1 mRNA-binding is stimulated by PABPC1 protein. Prevents BTRC/FBW1A mRNA degradation by disrupting microRNA-dependent interaction with AGO2. Promotes the directed movement of tumor-derived cells by fine-tuning intracellular signaling networks. Binds to MAPK4 3'-UTR and inhibits its translation. Interacts with PTEN transcript open reading frame (ORF) and prevents mRNA decay. This combined action on MAPK4 (down-regulation) and PTEN (up-regulation) antagonizes HSPB1 phosphorylation, consequently it prevents G-actin sequestration by phosphorylated HSPB1, allowing F-actin polymerization. Hence enhances the velocity of cell migration and stimulates directed cell migration by PTEN-modulated polarization. Interacts with Hepatitis C virus (HCV) 5'-UTR and 3'-UTR and specifically enhances translation at the HCV IRES, but not 5'-cap-dependent translation, possibly by recruiting eIF3. Interacts with HIV-1 GAG protein and blocks the formation of infectious HIV-1 particles. Reduces HIV-1 assembly by inhibiting viral RNA packaging, as well as assembly and processing of GAG protein on cellular membranes. During cellular stress, such as oxidative stress or heat shock, stabilizes target mRNAs that are recruited to stress granules, including CD44, IGF2, MAPK4, MYC, PTEN, RAPGEF2 and RPS6KA5 transcripts.
• Tissue Specificity: Mainly expressed in the embryo, including in fetal liver, fetal lung, fetal kidney, fetal thymus (at protein level). Also expressed follicles of ovary, as well as in gonocytes of testis, spermatogonia, semen, oocytes and placenta (at protein level). Expressed in various cancers, including testis and lung cancers (at protein level), as well as kidney, prostate and trachea cancers.
• KEGG Pathway: MicroR.s in cancer (hsa05206)
• Reactome Pathway:
  MAPK6/MAPK4 signaling (R-HSA-5687128)
  Insulin-like Growth Factor-2 mRNA Binding Proteins (IGF2BPs/IMPs/VICKZs) bind RNA (R-HSA-428359)

Molecular Interaction Atlas (MIA) of This DOT

47 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Definitive	Altered Expression	[1]
Meningioma	DISPT4TG	Definitive	Biomarker	[2]
Acute myelogenous leukaemia	DISCSPTN	Strong	Biomarker	[3]
Adenocarcinoma	DIS3IHTY	Strong	Altered Expression	[4]
B-cell neoplasm	DISVY326	Strong	Altered Expression	[5]
Bladder cancer	DISUHNM0	Strong	Altered Expression	[6]
Bone osteosarcoma	DIST1004	Strong	Biomarker	[7]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[8]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[8]
Carcinoma	DISH9F1N	Strong	Altered Expression	[9]
Cervical cancer	DISFSHPF	Strong	Biomarker	[10]
Cervical carcinoma	DIST4S00	Strong	Biomarker	[10]
Childhood acute lymphoblastic leukemia	DISJ5D6U	Strong	Genetic Variation	[11]
Clear cell renal carcinoma	DISBXRFJ	Strong	Altered Expression	[12]
Colon cancer	DISVC52G	Strong	Biomarker	[13]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[13]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[14]
Glioma	DIS5RPEH	Strong	Altered Expression	[15]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[16]
leukaemia	DISS7D1V	Strong	Altered Expression	[17]
Leukemia	DISNAKFL	Strong	Altered Expression	[17]
Lung adenocarcinoma	DISD51WR	Strong	Biomarker	[4]
Lung cancer	DISCM4YA	Strong	Altered Expression	[18]
Lung carcinoma	DISTR26C	Strong	Altered Expression	[18]
Lung neoplasm	DISVARNB	Strong	Altered Expression	[19]
Melanoma	DIS1RRCY	Strong	Biomarker	[20]
Metastatic malignant neoplasm	DIS86UK6	Strong	Altered Expression	[4]
Metastatic melanoma	DISSL43L	Strong	Altered Expression	[21]
Neoplasm	DISZKGEW	Strong	Biomarker	[20]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[22]
Osteosarcoma	DISLQ7E2	Strong	Biomarker	[7]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[14]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[14]
Prostate carcinoma	DISMJPLE	Strong	Altered Expression	[23]
Renal cell carcinoma	DISQZ2X8	Strong	Altered Expression	[12]
Urinary bladder cancer	DISDV4T7	Strong	Altered Expression	[6]
Urinary bladder neoplasm	DIS7HACE	Strong	Altered Expression	[6]
Coronary heart disease	DIS5OIP1	moderate	Genetic Variation	[24]
Pancreatic cancer	DISJC981	moderate	Altered Expression	[25]
Acute lymphocytic leukaemia	DISPX75S	Limited	Genetic Variation	[26]
Colorectal carcinoma	DIS5PYL0	Limited	Biomarker	[27]
Hepatitis C virus infection	DISQ0M8R	Limited	Biomarker	[28]
Liver cancer	DISDE4BI	Limited	Biomarker	[29]
Lymphoma	DISN6V4S	Limited	Altered Expression	[30]
Nasopharyngeal carcinoma	DISAOTQ0	Limited	Altered Expression	[31]
Neuroblastoma	DISVZBI4	Limited	Biomarker	[32]
Non-insulin dependent diabetes	DISK1O5Z	Limited	Genetic Variation	[33]

13 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 Insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1).	[34]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1).	[35]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1).	[36]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1).	[37]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1).	[38]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1).	[39]
Marinol	DM70IK5	Approved	Marinol increases the expression of Insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1).	[41]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1).	[43]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1).	[44]
CPI-0610	DMPXOYJ	Phase 3	CPI-0610 decreases the expression of Insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1).	[45]
INCB057643	DMG65CV	Phase 1/2	INCB057643 decreases the expression of Insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1).	[45]
Mivebresib	DMCPF90	Phase 1	Mivebresib decreases the expression of Insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1).	[45]
SB-431542	DM0YOXQ	Preclinical	SB-431542 increases the expression of Insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1).	[48]

4 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 Insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1).	[40]
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1).	[42]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1).	[46]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1).	[47]

References

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• [16] A novel, liver-specific long noncoding RNA LINC01093 suppresses HCC progression by interaction with IGF2BP1 to facilitate decay of GLI1 mRNA.Cancer Lett. 2019 May 28;450:98-109. doi: 10.1016/j.canlet.2019.02.033. Epub 2019 Feb 18.
• [17] RNA-binding protein IGF2BP1 maintains leukemia stem cell properties by regulating HOXB4, MYB, and ALDH1A1.Leukemia. 2020 May;34(5):1354-1363. doi: 10.1038/s41375-019-0656-9. Epub 2019 Nov 25.
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• [19] Increased expression of insulin-like growth factor-II messenger RNA-binding protein 1 is associated with tumor progression in patients with lung cancer.Clin Cancer Res. 2007 Jan 15;13(2 Pt 1):434-42. doi: 10.1158/1078-0432.CCR-06-1297.
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