Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTCAY35T)

• DOT Name: Cytoplasmic FMR1-interacting protein 2 (CYFIP2)
• Synonyms: p53-inducible protein 121
• Gene Name: CYFIP2
• Related Disease:
  Developmental and epileptic encephalopathy, 76
  Advanced cancer
  Autism
  Brain disease
  Breast cancer
  Breast carcinoma
  Chronic obstructive pulmonary disease
  Colon cancer
  Colon carcinoma
  Dementia
  Developmental and epileptic encephalopathy, 65
  Infantile epileptic-dyskinetic encephalopathy
  Intellectual disability
  Malignant soft tissue neoplasm
  Neoplasm
  Nervous system disease
  Neurodevelopmental disorder
  Sarcoma
  Schizophrenia
  Fragile X syndrome
  Small lymphocytic lymphoma
  Undetermined early-onset epileptic encephalopathy
  Amyotrophic lateral sclerosis
  Asthma
  Retinoblastoma
• UniProt ID: CYFP2_HUMAN
• Pfam ID: PF07159 ; PF05994
• Sequence:
  MTTHVTLEDALSNVDLLEELPLPDQQPCIEPPPSSIMYQANFDTNFEDRNAFVTGIARYI
  EQATVHSSMNEMLEEGHEYAVMLYTWRSCSRAIPQVKCNEQPNRVEIYEKTVEVLEPEVT
  KLMKFMYFQRKAIERFCSEVKRLCHAERRKDFVSEAYLLTLGKFINMFAVLDELKNMKCS
  VKNDHSAYKRAAQFLRKMADPQSIQESQNLSMFLANHNRITQCLHQQLEVIPGYEELLAD
  IVNICVDYYENKMYLTPSEKHMLLKVMGFGLYLMDGNVSNIYKLDAKKRINLSKIDKFFK
  QLQVVPLFGDMQIELARYIKTSAHYEENKSKWTCTQSSISPQYNICEQMVQIRDDHIRFI
  SELARYSNSEVVTGSGLDSQKSDEEYRELFDLALRGLQLLSKWSAHVMEVYSWKLVHPTD
  KFCNKDCPGTAEEYERATRYNYTSEEKFAFVEVIAMIKGLQVLMGRMESVFNQAIRNTIY
  AALQDFAQVTLREPLRQAVRKKKNVLISVLQAIRKTICDWEGGREPPNDPCLRGEKDPKG
  GFDIKVPRRAVGPSSTQACQWSPRALFHPTGGTQGRRGCRSLLYMVRTMLESLIADKSGS
  KKTLRSSLDGPIVLAIEDFHKQSFFFTHLLNISEALQQCCDLSQLWFREFFLELTMGRRI
  QFPIEMSMPWILTDHILETKEPSMMEYVLYPLDLYNDSAYYALTKFKKQFLYDEIEAEVN
  LCFDQFVYKLADQIFAYYKAMAGSVLLDKRFRAECKNYGVIIPYPPSNRYETLLKQRHVQ
  LLGRSIDLNRLITQRISAAMYKSLDQAISRFESEDLTSIVELEWLLEINRLTHRLLCKHM
  TLDSFDAMFREANHNVSAPYGRITLHVFWELNFDFLPNYCYNGSTNRFVRTAIPFTQEPQ
  RDKPANVQPYYLYGSKPLNIAYSHIYSSYRNFVGPPHFKTICRLLGYQGIAVVMEELLKI
  VKSLLQGTILQYVKTLIEVMPKICRLPRHEYGSPGILEFFHHQLKDIIEYAELKTDVFQS
  LREVGNAILFCLLIEQALSQEEVCDLLHAAPFQNILPRVYIKEGERLEVRMKRLEAKYAP
  LHLVPLIERLGTPQQIAIAREGDLLTKERLCCGLSMFEVILTRIRSYLQDPIWRGPPPTN
  GVMHVDECVEFHRLWSAMQFVYCIPVGTNEFTAEQCFGDGLNWAGCSIIVLLGQQRRFDL
  FDFCYHLLKVQRQDGKDEIIKNVPLKKMADRIRKYQILNNEVFAILNKYMKSVETDSSTV
  EHVRCFQPPIHQSLATTC
• Function: Involved in T-cell adhesion and p53/TP53-dependent induction of apoptosis. Does not bind RNA. As component of the WAVE1 complex, required for BDNF-NTRK2 endocytic trafficking and signaling from early endosomes.
• Tissue Specificity: Expressed in T-cells. Increased expression is observed in CD4(+) T-lymphocytes from patients with multiple sclerosis (at protein level).
• KEGG Pathway:
  Regulation of actin cytoskeleton (hsa04810)
  Pathogenic Escherichia coli infection (hsa05130)
  Salmonella infection (hsa05132)
• Reactome Pathway:
  VEGFA-VEGFR2 Pathway (R-HSA-4420097)
  RHO GTPases Activate WASPs and WAVEs (R-HSA-5663213)
  RAC1 GTPase cycle (R-HSA-9013149)
  FCGR3A-mediated phagocytosis (R-HSA-9664422)
  Regulation of actin dynamics for phagocytic cup formation (R-HSA-2029482)

Molecular Interaction Atlas (MIA) of This DOT

25 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Developmental and epileptic encephalopathy, 76	DISH4XWH	Definitive	Autosomal dominant	[1]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[2]
Autism	DISV4V1Z	Strong	Biomarker	[3]
Brain disease	DIS6ZC3X	Strong	Biomarker	[4]
Breast cancer	DIS7DPX1	Strong	Genetic Variation	[5]
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[5]
Chronic obstructive pulmonary disease	DISQCIRF	Strong	Genetic Variation	[6]
Colon cancer	DISVC52G	Strong	Biomarker	[7]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[7]
Dementia	DISXL1WY	Strong	Altered Expression	[8]
Developmental and epileptic encephalopathy, 65	DISOSZDB	Strong	Autosomal dominant	[9]
Infantile epileptic-dyskinetic encephalopathy	DISD2ZNC	Strong	Biomarker	[4]
Intellectual disability	DISMBNXP	Strong	Genetic Variation	[3]
Malignant soft tissue neoplasm	DISTC6NO	Strong	Biomarker	[10]
Neoplasm	DISZKGEW	Strong	Genetic Variation	[11]
Nervous system disease	DISJ7GGT	Strong	Biomarker	[4]
Neurodevelopmental disorder	DIS372XH	Strong	Biomarker	[3]
Sarcoma	DISZDG3U	Strong	Biomarker	[10]
Schizophrenia	DISSRV2N	Strong	Altered Expression	[8]
Fragile X syndrome	DISE8W3A	moderate	Biomarker	[4]
Small lymphocytic lymphoma	DIS30POX	moderate	Biomarker	[12]
Undetermined early-onset epileptic encephalopathy	DISISEI2	Supportive	Autosomal dominant	[9]
Amyotrophic lateral sclerosis	DISF7HVM	Limited	Biomarker	[13]
Asthma	DISW9QNS	Limited	Biomarker	[14]
Retinoblastoma	DISVPNPB	Limited	Biomarker	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Cytoplasmic FMR1-interacting protein 2 (CYFIP2).	[15]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Cytoplasmic FMR1-interacting protein 2 (CYFIP2).	[26]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Cytoplasmic FMR1-interacting protein 2 (CYFIP2).	[27]

13 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 Cytoplasmic FMR1-interacting protein 2 (CYFIP2).	[16]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Cytoplasmic FMR1-interacting protein 2 (CYFIP2).	[17]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Cytoplasmic FMR1-interacting protein 2 (CYFIP2).	[18]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Cytoplasmic FMR1-interacting protein 2 (CYFIP2).	[19]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Cytoplasmic FMR1-interacting protein 2 (CYFIP2).	[20]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Cytoplasmic FMR1-interacting protein 2 (CYFIP2).	[21]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Cytoplasmic FMR1-interacting protein 2 (CYFIP2).	[22]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Cytoplasmic FMR1-interacting protein 2 (CYFIP2).	[23]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of Cytoplasmic FMR1-interacting protein 2 (CYFIP2).	[24]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil increases the expression of Cytoplasmic FMR1-interacting protein 2 (CYFIP2).	[25]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Cytoplasmic FMR1-interacting protein 2 (CYFIP2).	[28]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Cytoplasmic FMR1-interacting protein 2 (CYFIP2).	[29]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Cytoplasmic FMR1-interacting protein 2 (CYFIP2).	[30]

References

• [1] Novel West syndrome candidate genes in a Chinese cohort. CNS Neurosci Ther. 2018 Dec;24(12):1196-1206. doi: 10.1111/cns.12860. Epub 2018 Apr 17.
• [2] The roles of p53R2 in cancer progression based on the new function of mutant p53 and cytoplasmic p21.Life Sci. 2014 Mar 18;99(1-2):14-7. doi: 10.1016/j.lfs.2014.01.063. Epub 2014 Jan 28.
• [3] Spatially clustering de novo variants in CYFIP2, encoding the cytoplasmic FMRP interacting protein 2, cause intellectual disability and seizures.Eur J Hum Genet. 2019 May;27(5):747-759. doi: 10.1038/s41431-018-0331-z. Epub 2019 Jan 21.
• [4] Neuronal function and dysfunction of CYFIP2: from actin dynamics to early infantile epileptic encephalopathy.BMB Rep. 2019 May;52(5):304-311. doi: 10.5483/BMBRep.2019.52.5.097.
• [5] Mosaic PPM1D mutations are associated with predisposition to breast and ovarian cancer. Nature. 2013 Jan 17;493(7432):406-10. doi: 10.1038/nature11725. Epub 2012 Dec 16.
• [6] Association between the p21 codon 31 A1 (arg) allele and lung cancer.Hum Hered. 1996 Jul-Aug;46(4):221-5. doi: 10.1159/000154357.
• [7] IMP-1 displays cross-talk with K-Ras and modulates colon cancer cell survival through the novel proapoptotic protein CYFIP2.Cancer Res. 2011 Mar 15;71(6):2172-82. doi: 10.1158/0008-5472.CAN-10-3295. Epub 2011 Jan 20.
• [8] Cell cycle checkpoint abnormalities during dementia: A plausible association with the loss of protection against oxidative stress in Alzheimer's disease [corrected].PLoS One. 2013 Jul 5;8(7):e68361. doi: 10.1371/journal.pone.0068361. Print 2013.
• [9] De novo hotspot variants in CYFIP2 cause early-onset epileptic encephalopathy. Ann Neurol. 2018 Apr;83(4):794-806. doi: 10.1002/ana.25208.
• [10] MDM2 and p21WAF1/CIP1, wild-type p53-induced proteins, are regularly expressed by Sternberg-Reed cells in Hodgkin's disease.J Pathol. 1996 Sep;180(1):58-64. doi: 10.1002/(SICI)1096-9896(199609)180:1<58::AID-PATH610>3.0.CO;2-W.
• [11] Hotspot DAXX, PTCH2 and CYFIP2 mutations in pancreatic neuroendocrine neoplasms.Endocr Relat Cancer. 2019 Jan 1;26(1):1-12. doi: 10.1530/ERC-18-0120.
• [12] Mantle cell lymphoma displays a homogenous methylation profile: a comparative analysis with chronic lymphocytic leukemia.Am J Hematol. 2012 Apr;87(4):361-7. doi: 10.1002/ajh.23115. Epub 2012 Feb 28.
• [13] Two potential biomarkers identified in mesenchymal stem cells and leukocytes of patients with sporadic amyotrophic lateral sclerosis.Dis Markers. 2012;32(4):211-20. doi: 10.3233/DMA-2011-0885.
• [14] Analyses of associations between three positionally cloned asthma candidate genes and asthma or asthma-related phenotypes in a Chinese population.BMC Med Genet. 2009 Dec 1;10:123. doi: 10.1186/1471-2350-10-123.
• [15] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [16] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [17] Systems analysis of transcriptome and proteome in retinoic acid/arsenic trioxide-induced cell differentiation/apoptosis of promyelocytic leukemia. Proc Natl Acad Sci U S A. 2005 May 24;102(21):7653-8.
• [18] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [19] 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.
• [20] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [21] 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.
• [22] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [23] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [24] Unique transcriptome, pathways, and networks in the human endometrial fibroblast response to progesterone in endometriosis. Biol Reprod. 2011 Apr;84(4):801-15.
• [25] Gene expression profiling of breast cancer cells in response to gemcitabine: NF-kappaB pathway activation as a potential mechanism of resistance. Breast Cancer Res Treat. 2007 Apr;102(2):157-72.
• [26] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [27] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [28] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [29] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [30] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.