Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTF91GTL)

DOT Name Pre-mRNA 3'-end-processing factor FIP1 (FIP1L1)
Synonyms hFip1; FIP1-like 1 protein; Factor interacting with PAP; Rearranged in hypereosinophilia
Gene Name FIP1L1
Related Disease
Advanced cancer ( )
Adult lymphoma ( )
Angioimmunoblastic T-cell Lymphoma ( )
Atopic dermatitis ( )
Cardiac failure ( )
Chronic eosinophilic leukemia ( )
Chronic myelomonocytic leukemia ( )
Congestive heart failure ( )
Essential thrombocythemia ( )
Haematological malignancy ( )
Leukemia ( )
Lymphoblastic lymphoma ( )
Lymphoma ( )
Myeloid leukaemia ( )
Myeloid neoplasm ( )
Myeloproliferative neoplasm ( )
Pediatric lymphoma ( )
Polycythemia vera ( )
Polymyalgia rheumatica ( )
Precursor T-lymphoblastic lymphoma/leukemia ( )
Primary myelofibrosis ( )
Promyelocytic leukaemia ( )
Psoriatic arthritis ( )
Rheumatoid arthritis ( )
T-cell lymphoma ( )
Trichohepatoenteric syndrome ( )
Chronic myelomonocytic leukaemia ( )
Gastrointestinal stromal tumour ( )
Mastocytosis ( )
Polyp ( )
Systemic mastocytosis ( )
Acute myelogenous leukaemia ( )
Acute leukaemia ( )
Anemia ( )
Blast phase chronic myelogenous leukemia, BCR-ABL1 positive ( )
Eosinophilic esophagitis ( )
leukaemia ( )
Neoplasm ( )
UniProt ID
FIP1_HUMAN
3D Structure
Download
2D Sequence (FASTA)
Download
3D Structure (PDB)
Download
PDB ID
7K95; 7ZY4; 7ZYH
Pfam ID
PF05182
Sequence
MSAGEVERLVSELSGGTGGDEEEEWLYGGPWDVHVHSDLAKDLDENEVERPEEENASANP
PSGIEDETAENGVPKPKVTETEDDSDSDSDDDEDDVHVTIGDIKTGAPQYGSYGTAPVNL
NIKTGGRVYGTTGTKVKGVDLDAPGSINGVPLLEVDLDSFEDKPWRKPGADLSDYFNYGF
NEDTWKAYCEKQKRIRMGLEVIPVTSTTNKITAEDCTMEVTPGAEIQDGRFNLFKVQQGR
TGNSEKETALPSTKAEFTSPPSLFKTGLPPSRNSTSSQSQTSTASRKANSSVGKWQDRYG
RAESPDLRRLPGAIDVIGQTITISRVEGRRRANENSNIQVLSERSATEVDNNFSKPPPFF
PPGAPPTHLPPPPFLPPPPTVSTAPPLIPPPGFPPPPGAPPPSLIPTIESGHSSGYDSRS
ARAFPYGNVAFPHLPGSAPSWPSLVDTSKQWDYYARREKDRDRERDRDRERDRDRDRERE
RTRERERERDHSPTPSVFNSDEERYRYREYAERGYERHRASREKEERHRERRHREKEETR
HKSSRSNSRRRHESEEGDSHRRHKHKKSKRSKEGKEAGSEPAPEQESTEATPAE
Function
Component of the cleavage and polyadenylation specificity factor (CPSF) complex that plays a key role in pre-mRNA 3'-end formation, recognizing the AAUAAA signal sequence and interacting with poly(A) polymerase and other factors to bring about cleavage and poly(A) addition. FIP1L1 contributes to poly(A) site recognition and stimulates poly(A) addition. Binds to U-rich RNA sequence elements surrounding the poly(A) site. May act to tether poly(A) polymerase to the CPSF complex.
KEGG Pathway
mR. surveillance pathway (hsa03015 )
Reactome Pathway
mRNA 3'-end processing (R-HSA-72187 )
Processing of Capped Intron-Containing Pre-mRNA (R-HSA-72203 )
RNA Polymerase II Transcription Termination (R-HSA-73856 )
Processing of Intronless Pre-mRNAs (R-HSA-77595 )
Signaling by cytosolic PDGFRA and PDGFRB fusion proteins (R-HSA-9673766 )
Transport of Mature mRNA Derived from an Intronless Transcript (R-HSA-159231 )

Molecular Interaction Atlas (MIA) of This DOT

38 Disease(s) Related to This DOT
Disease Name Disease ID Evidence Level Mode of Inheritance REF
Advanced cancer DISAT1Z9 Definitive Biomarker [1]
Adult lymphoma DISK8IZR Strong Biomarker [2]
Angioimmunoblastic T-cell Lymphoma DISZPFTL Strong Genetic Variation [2]
Atopic dermatitis DISTCP41 Strong Biomarker [3]
Cardiac failure DISDC067 Strong Biomarker [4]
Chronic eosinophilic leukemia DISAJOUO Strong Biomarker [5]
Chronic myelomonocytic leukemia DISIL8UR Strong Biomarker [6]
Congestive heart failure DIS32MEA Strong Biomarker [4]
Essential thrombocythemia DISWWK11 Strong Altered Expression [7]
Haematological malignancy DISCDP7W Strong Genetic Variation [8]
Leukemia DISNAKFL Strong Biomarker [9]
Lymphoblastic lymphoma DISB9ZYC Strong Biomarker [10]
Lymphoma DISN6V4S Strong Biomarker [2]
Myeloid leukaemia DISMN944 Strong Biomarker [11]
Myeloid neoplasm DIS2YOWO Strong Genetic Variation [12]
Myeloproliferative neoplasm DIS5KAPA Strong Genetic Variation [13]
Pediatric lymphoma DIS51BK2 Strong Biomarker [2]
Polycythemia vera DISB5FPO Strong Biomarker [14]
Polymyalgia rheumatica DIS5F36E Strong Genetic Variation [15]
Precursor T-lymphoblastic lymphoma/leukemia DISCZ298 Strong Biomarker [8]
Primary myelofibrosis DIS6L0CN Strong Altered Expression [7]
Promyelocytic leukaemia DISYGG13 Strong FusionGene [16]
Psoriatic arthritis DISLWTG2 Strong Biomarker [15]
Rheumatoid arthritis DISTSB4J Strong Biomarker [15]
T-cell lymphoma DISSXRTQ Strong Biomarker [17]
Trichohepatoenteric syndrome DISL3ODF Strong Biomarker [18]
Chronic myelomonocytic leukaemia DISDN5P7 moderate Altered Expression [7]
Gastrointestinal stromal tumour DIS6TJYS moderate Genetic Variation [19]
Mastocytosis DIS1TEE0 moderate Biomarker [20]
Polyp DISRSLYF moderate Genetic Variation [19]
Systemic mastocytosis DISNQ2OY moderate Biomarker [21]
Acute myelogenous leukaemia DISCSPTN Disputed Genetic Variation [13]
Acute leukaemia DISDQFDI Limited Biomarker [22]
Anemia DISTVL0C Limited Biomarker [23]
Blast phase chronic myelogenous leukemia, BCR-ABL1 positive DIS3KLUX Limited Biomarker [22]
Eosinophilic esophagitis DISR8WSB Limited Genetic Variation [24]
leukaemia DISS7D1V Limited Biomarker [9]
Neoplasm DISZKGEW Limited Genetic Variation [8]
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⏷ Show the Full List of 38 Disease(s)
Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This DOT
9 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 Pre-mRNA 3'-end-processing factor FIP1 (FIP1L1). [25]
Ciclosporin DMAZJFX Approved Ciclosporin increases the expression of Pre-mRNA 3'-end-processing factor FIP1 (FIP1L1). [26]
Doxorubicin DMVP5YE Approved Doxorubicin decreases the expression of Pre-mRNA 3'-end-processing factor FIP1 (FIP1L1). [27]
Ivermectin DMDBX5F Approved Ivermectin decreases the expression of Pre-mRNA 3'-end-processing factor FIP1 (FIP1L1). [28]
Hydrogen peroxide DM1NG5W Approved Hydrogen peroxide affects the expression of Pre-mRNA 3'-end-processing factor FIP1 (FIP1L1). [30]
Phenobarbital DMXZOCG Approved Phenobarbital affects the expression of Pre-mRNA 3'-end-processing factor FIP1 (FIP1L1). [31]
Menadione DMSJDTY Approved Menadione affects the expression of Pre-mRNA 3'-end-processing factor FIP1 (FIP1L1). [32]
PMID28460551-Compound-2 DM4DOUB Patented PMID28460551-Compound-2 increases the expression of Pre-mRNA 3'-end-processing factor FIP1 (FIP1L1). [35]
Bisphenol A DM2ZLD7 Investigative Bisphenol A decreases the expression of Pre-mRNA 3'-end-processing factor FIP1 (FIP1L1). [37]
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⏷ Show the Full List of 9 Drug(s)
5 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 Pre-mRNA 3'-end-processing factor FIP1 (FIP1L1). [29]
Dasatinib DMJV2EK Approved Dasatinib decreases the phosphorylation of Pre-mRNA 3'-end-processing factor FIP1 (FIP1L1). [33]
TAK-243 DM4GKV2 Phase 1 TAK-243 decreases the sumoylation of Pre-mRNA 3'-end-processing factor FIP1 (FIP1L1). [34]
PMID28870136-Compound-52 DMFDERP Patented PMID28870136-Compound-52 affects the phosphorylation of Pre-mRNA 3'-end-processing factor FIP1 (FIP1L1). [36]
Coumarin DM0N8ZM Investigative Coumarin affects the phosphorylation of Pre-mRNA 3'-end-processing factor FIP1 (FIP1L1). [36]
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References

1 ETV6-PDGFRB and FIP1L1-PDGFRA stimulate human hematopoietic progenitor cell proliferation and differentiation into eosinophils: the role of nuclear factor-B.Haematologica. 2012 Jul;97(7):1064-72. doi: 10.3324/haematol.2011.047530. Epub 2012 Jan 22.
2 Angioimmunoblastic T-cell lymphoma and hypereosinophilic syndrome with FIP1L1/PDGFRA fusion gene effectively treated with imatinib: A case report.Medicine (Baltimore). 2017 Sep;96(36):e8001. doi: 10.1097/MD.0000000000008001.
3 IL-1 induces thymic stromal lymphopoietin and an atopic dermatitis-like phenotype in reconstructed healthy human epidermis.J Pathol. 2017 Jun;242(2):234-245. doi: 10.1002/path.4887. Epub 2017 Apr 6.
4 Hypereosinophilic Syndrome as a Rare Cause of Reversible Biventricular Heart Failure.Can J Cardiol. 2017 May;33(5):688.e5-688.e7. doi: 10.1016/j.cjca.2017.01.006. Epub 2017 Jan 20.
5 Leukemogenic kinase FIP1L1-PDGFRA and a small ubiquitin-like modifier E3 ligase, PIAS1, form a positive cross-talk through their enzymatic activities.Cancer Sci. 2017 Feb;108(2):200-207. doi: 10.1111/cas.13129.
6 Discovery of imatinib-responsive FIP1L1-PDGFRA mutation during refractory acute myeloid leukemia transformation of chronic myelomonocytic leukemia.J Hematol Oncol. 2014 Mar 27;7:26. doi: 10.1186/1756-8722-7-26.
7 Oncogenes in myeloproliferative disorders.Cell Cycle. 2007 Mar 1;6(5):550-66. doi: 10.4161/cc.6.5.3919. Epub 2007 Mar 24.
8 A neoplasm with FIP1L1-PDGFRA fusion presenting as pediatric T-cell lymphoblastic leukemia/lymphoma without eosinophilia.Cancer Genet. 2017 Oct;216-217:91-99. doi: 10.1016/j.cancergen.2017.07.007. Epub 2017 Aug 3.
9 FIP1L1 presence in FIP1L1-RARA or FIP1L1-PDGFRA differentially contributes to the pathogenesis of distinct types of leukemia.Ann Hematol. 2014 Sep;93(9):1473-81. doi: 10.1007/s00277-014-2085-1. Epub 2014 Apr 25.
10 Synchronous FIP1L1-PDGFRA-positive chronic eosinophilic leukemia and T-cell lymphoblastic lymphoma: a bilineal clonal malignancy.Eur J Haematol. 2008 Jan;80(1):81-6. doi: 10.1111/j.1600-0609.2007.00973.x. Epub 2007 Nov 19.
11 Complete and long-lasting cytologic and molecular remission of FIP1L1-PDGFRA-positive acute eosinophil myeloid leukaemia, treated with low-dose imatinib monotherapy.Eur J Haematol. 2014 Jun;92(6):541-5. doi: 10.1111/ejh.12272. Epub 2014 Feb 19.
12 Myeloid neoplasm with eosinophilia associated with isolated extramedullary FIP1L1/PDGFRA rearrangement.Cancer Genet. 2018 Jan;220:13-18. doi: 10.1016/j.cancergen.2017.10.004. Epub 2017 Oct 23.
13 Atypical Phenotype and Treatment Response Pattern in a Patient with FIP1L1-PDGFR Mutation.Acta Haematol. 2018;140(2):67-70. doi: 10.1159/000492485. Epub 2018 Sep 5.
14 Case of polycythemia vera concurrent with FIP1L1-PDGFRA-positive myeloproliferative neoplasm with eosinophilia.Cancer Genet. 2012 Oct;205(10):519-22. doi: 10.1016/j.cancergen.2012.05.010. Epub 2012 Sep 1.
15 Incidence of rheumatoid arthritis, psoriatic arthritis and polymyalgia rheumatica in an inland area of central Italy: results of the CAMPO-RHE study.Postgrad Med. 2018 Jan;130(1):137-141. doi: 10.1080/00325481.2018.1399774. Epub 2017 Nov 3.
16 The seventh pathogenic fusion gene FIP1L1-RARA was isolated from a t(4;17)-positive acute promyelocytic leukemia.Haematologica. 2008 Sep;93(9):1414-6. doi: 10.3324/haematol.12854. Epub 2008 Jul 4.
17 Recurrent finding of the FIP1L1-PDGFRA fusion gene in eosinophilia-associated acute myeloid leukemia and lymphoblastic T-cell lymphoma.Leukemia. 2007 Jun;21(6):1183-8. doi: 10.1038/sj.leu.2404662. Epub 2007 Mar 22.
18 A tyrosine kinase created by fusion of the PDGFRA and FIP1L1 genes as a therapeutic target of imatinib in idiopathic hypereosinophilic syndrome.N Engl J Med. 2003 Mar 27;348(13):1201-14. doi: 10.1056/NEJMoa025217.
19 The tyrosine phosphatase SHP2 is required for cell transformation by the receptor tyrosine kinase mutants FIP1L1-PDGFR and PDGFR D842V.Mol Oncol. 2014 May;8(3):728-40. doi: 10.1016/j.molonc.2014.02.003. Epub 2014 Feb 17.
20 A comprehensive review of imatinib mesylate (Gleevec) for dermatological diseases.J Drugs Dermatol. 2006 Feb;5(2):117-22.
21 Mast cells and eosinophils in mastocytosis, chronic eosinophilic leukemia, and non-clonal disorders.Semin Hematol. 2012 Apr;49(2):128-37. doi: 10.1053/j.seminhematol.2012.01.007.
22 Hes1 upregulation contributes to the development of FIP1L1-PDGRA-positive leukemia in blast crisis.Exp Hematol. 2014 May;42(5):369-379.e3. doi: 10.1016/j.exphem.2014.01.009. Epub 2014 Jan 31.
23 Response to imatinib mesylate in patients with hypereosinophilic syndrome.Int J Hematol. 2012 Sep;96(3):320-6. doi: 10.1007/s12185-012-1141-7. Epub 2012 Jul 18.
24 Markers of tyrosine kinase activity in eosinophilic esophagitis: a pilot study of the FIP1L1-PDGFR fusion gene, pERK 1/2, and pSTAT5.Dis Esophagus. 2012 Feb;25(2):166-74. doi: 10.1111/j.1442-2050.2011.01230.x. Epub 2011 Aug 5.
25 Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
26 Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
27 Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
28 Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
29 Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
30 Minimal peroxide exposure of neuronal cells induces multifaceted adaptive responses. PLoS One. 2010 Dec 17;5(12):e14352. doi: 10.1371/journal.pone.0014352.
31 Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
32 Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
33 Dasatinib inhibits the growth and survival of neoplastic human eosinophils (EOL-1) through targeting of FIP1L1-PDGFRalpha. Exp Hematol. 2008 Oct;36(10):1244-53. doi: 10.1016/j.exphem.2008.04.017. Epub 2008 Jul 10.
34 Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
35 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.
36 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.
37 Isobaric tags for relative and absolute quantitation-based proteomics analysis of the effect of ginger oil on bisphenol A-induced breast cancer cell proliferation. Oncol Lett. 2021 Feb;21(2):101. doi: 10.3892/ol.2020.12362. Epub 2020 Dec 8.