{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T03:03:44Z","timestamp":1785207824905,"version":"3.55.0"},"reference-count":56,"publisher":"Elsevier BV","license":[{"start":{"date-parts":[[2024,8,1]],"date-time":"2024-08-01T00:00:00Z","timestamp":1722470400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/tdm\/userlicense\/1.0\/"},{"start":{"date-parts":[[2024,8,1]],"date-time":"2024-08-01T00:00:00Z","timestamp":1722470400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/legal\/tdmrep-license"},{"start":{"date-parts":[[2024,7,9]],"date-time":"2024-07-09T00:00:00Z","timestamp":1720483200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["clinicalkey.fr","clinicalkey.jp","clinicalkey.es","clinicalkey.com.au","bmn.com","clinicalkey.com","elsevier.com","sciencedirect.com"],"crossmark-restriction":true},"short-container-title":["Current Opinion in Genetics &amp; Development"],"published-print":{"date-parts":[[2024,8]]},"DOI":"10.1016\/j.gde.2024.102230","type":"journal-article","created":{"date-parts":[[2024,7,17]],"date-time":"2024-07-17T22:39:09Z","timestamp":1721255949000},"page":"102230","update-policy":"https:\/\/doi.org\/10.1016\/elsevier_cm_policy","source":"Crossref","is-referenced-by-count":7,"special_numbering":"C","title":["Therapeutic strategies to target the epitranscriptomic machinery"],"prefix":"10.1016","volume":"87","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4950-7254","authenticated-orcid":false,"given":"Denise","family":"Sighel","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3804-6712","authenticated-orcid":false,"given":"Eliana","family":"Destefanis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3333-7630","authenticated-orcid":false,"given":"Alessandro","family":"Quattrone","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"78","reference":[{"key":"10.1016\/j.gde.2024.102230_bib1","doi-asserted-by":"crossref","first-page":"D231","DOI":"10.1093\/nar\/gkab1083","article-title":"MODOMICS: a database of RNA modification pathways. 2021 update","volume":"50","author":"Boccaletto","year":"2022","journal-title":"Nucleic Acids Res"},{"key":"10.1016\/j.gde.2024.102230_bib2","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1038\/nature11112","article-title":"Topology of the human and mouse m6A RNA methylomes revealed by m6A-seq","volume":"485","author":"Dominissini","year":"2012","journal-title":"Nature"},{"key":"10.1016\/j.gde.2024.102230_bib3","doi-asserted-by":"crossref","first-page":"1635","DOI":"10.1016\/j.cell.2012.05.003","article-title":"Comprehensive analysis of mRNA methylation reveals enrichment in 3\u2032 UTRs and near stop codons","volume":"149","author":"Meyer","year":"2012","journal-title":"Cell"},{"key":"10.1016\/j.gde.2024.102230_bib4","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1146\/annurev-biochem-052521-035330","article-title":"The proteins of mRNA modification: writers, readers, and erasers","volume":"92","author":"Flamand","year":"2023","journal-title":"Annu Rev Biochem"},{"key":"10.1016\/j.gde.2024.102230_bib5","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1016\/j.tig.2022.10.004","article-title":"Genetic and epigenetic defects of the RNA modification machinery in cancer","volume":"39","author":"Orsolic","year":"2023","journal-title":"Trends Genet"},{"key":"10.1016\/j.gde.2024.102230_bib6","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1038\/s41576-023-00645-2","article-title":"RNA modifications in physiology and disease: towards clinical applications","volume":"25","author":"Delaunay","year":"2024","journal-title":"Nat Rev Genet"},{"key":"10.1016\/j.gde.2024.102230_bib7","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1038\/nature18298","article-title":"Structural basis of N(6)-adenosine methylation by the METTL3-METTL14 complex","volume":"534","author":"Wang","year":"2016","journal-title":"Nature"},{"key":"10.1016\/j.gde.2024.102230_bib8","doi-asserted-by":"crossref","first-page":"1205","DOI":"10.1038\/nature08921","article-title":"Crystal structure of the FTO protein reveals basis for its substrate specificity","volume":"464","author":"Han","year":"2010","journal-title":"Nature"},{"key":"10.1016\/j.gde.2024.102230_bib9","doi-asserted-by":"crossref","first-page":"11571","DOI":"10.1074\/jbc.M113.546168","article-title":"Crystal structures of the human RNA demethylase Alkbh5 reveal basis for substrate recognition","volume":"289","author":"Feng","year":"2014","journal-title":"J Biol Chem"},{"key":"10.1016\/j.gde.2024.102230_bib10","doi-asserted-by":"crossref","first-page":"5932","DOI":"10.1021\/acs.jcim.0c01029","article-title":"Structural and dynamic insights into redundant function of YTHDF proteins","volume":"60","author":"Li","year":"2020","journal-title":"J Chem Inf Model"},{"key":"10.1016\/j.gde.2024.102230_bib11","doi-asserted-by":"crossref","first-page":"1654","DOI":"10.1021\/acs.jmedchem.2c01601","article-title":"METTL3 from target validation to the first small-molecule inhibitors: a medicinal chemistry journey","volume":"66","author":"Fiorentino","year":"2023","journal-title":"J Med Chem"},{"key":"10.1016\/j.gde.2024.102230_bib12","doi-asserted-by":"crossref","first-page":"12738","DOI":"10.1021\/acs.jmedchem.1c00773","article-title":"1,4,9-Triazaspiro[5.5]undecan-2-one derivatives as potent and selective METTL3 iInhibitors","volume":"64","author":"Dolbois","year":"2021","journal-title":"J Med Chem"},{"key":"10.1016\/j.gde.2024.102230_sbref13","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1038\/s41586-021-03536-w","article-title":"Small-molecule inhibition of METTL3 as a strategy against myeloid leukaemia","volume":"593","author":"Yankova","year":"2021","journal-title":"Nature"},{"key":"10.1016\/j.gde.2024.102230_bib14","doi-asserted-by":"crossref","first-page":"718","DOI":"10.1111\/imcb.12581","article-title":"METTL3 inhibition reduces N6 -methyladenosine levels and prevents allogeneic CD4+ T-cell responses","volume":"100","author":"Li","year":"2022","journal-title":"Immunol Cell Biol"},{"key":"10.1016\/j.gde.2024.102230_bib15","unstructured":"Mills JEJ, MH Daniels, TA Wynn, BA Sparling, EA Sickmier, AS Tasker: METTL3 Modulators; World Patent. 2022. (No. 2022081739:A1). Available at: \u3008https:\/\/patentimages.storage.googleapis.com\/9c\/46\/92\/0214b090ce8626\/WO2022081739A1.pdf\u3009."},{"key":"10.1016\/j.gde.2024.102230_bib16","unstructured":"WP Blackaby, DJ Hardick, EJ Thomas, FA Brookfield, J Shepherd, C Bubert, MP Ridgill: Polyheterocyclic Compounds as METTL3 Inhibitors; World Patent. 2021. (No. 2021111124:A1). Available at: \u3008https:\/\/patentimages.storage.googleapis.com\/47\/d2\/d9\/e99d5905f3ab34\/WO2021111124A1.pdf\u3009."},{"key":"10.1016\/j.gde.2024.102230_bib17","doi-asserted-by":"crossref","first-page":"2133","DOI":"10.1038\/s41375-023-01965-2","article-title":"Pharmacological inhibition of METTL3 impacts specific haematopoietic lineages","volume":"37","author":"Sturgess","year":"2023","journal-title":"Leukemia"},{"key":"10.1016\/j.gde.2024.102230_bib18","first-page":"783","article-title":"Discovery of substituted indole derivatives as allosteric inhibitors of m6 A-RNA methyltransferase, METTL3-14 complex","volume":"83","author":"Lee","year":"2022","journal-title":"Drug Dev Res"},{"key":"10.1016\/j.gde.2024.102230_bib19","doi-asserted-by":"crossref","first-page":"440","DOI":"10.3390\/ph15040440","article-title":"Eltrombopag as an allosteric inhibitor of the METTL3-14 complex affecting the m6A methylation of RNA in acute myeloid leukemia cells","volume":"15","author":"Lee","year":"2022","journal-title":"Pharmaceuticals"},{"key":"10.1016\/j.gde.2024.102230_sbref18","doi-asserted-by":"crossref","DOI":"10.7554\/eLife.92537","article-title":"The catalytic mechanism of the RNA methyltransferase METTL3","volume":"12","author":"Corbeski","year":"2024","journal-title":"Elife"},{"key":"10.1016\/j.gde.2024.102230_bib21","doi-asserted-by":"crossref","first-page":"885","DOI":"10.1038\/nchembio.687","article-title":"N6-methyladenosine in nuclear RNA is a major substrate of the obesity-associated FTO","volume":"7","author":"Jia","year":"2011","journal-title":"Nat Chem Biol"},{"key":"10.1016\/j.gde.2024.102230_bib22","doi-asserted-by":"crossref","first-page":"2919","DOI":"10.1073\/pnas.1820574116","article-title":"Structural insights into FTO\u2019s catalytic mechanism for the demethylation of multiple RNA substrates","volume":"116","author":"Zhang","year":"2019","journal-title":"Proc Natl Acad Sci"},{"key":"10.1016\/j.gde.2024.102230_bib23","doi-asserted-by":"crossref","first-page":"17963","DOI":"10.1021\/ja3064149","article-title":"Development of cell-active N6-methyladenosine RNA demethylase FTO inhibitor","volume":"134","author":"Chen","year":"2012","journal-title":"J Am Chem Soc"},{"key":"10.1016\/j.gde.2024.102230_bib24","doi-asserted-by":"crossref","first-page":"3010","DOI":"10.1021\/acs.accounts.3c00451","article-title":"Chemical inhibitors targeting the oncogenic m6A modifying proteins","volume":"56","author":"Huang","year":"2023","journal-title":"Acc Chem Res"},{"key":"10.1016\/j.gde.2024.102230_bib25","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1016\/j.ccell.2020.04.017","article-title":"Targeting FTO suppresses cancer stem cell maintenance and immune evasion","volume":"38","author":"Su","year":"2020","journal-title":"Cancer Cell"},{"key":"10.1016\/j.gde.2024.102230_sbref24","doi-asserted-by":"crossref","first-page":"9731","DOI":"10.1021\/acs.jmedchem.3c00543","article-title":"Rational Design of RNA Demethylase FTO inhibitors with enhanced antileukemia drug-like properties","volume":"66","author":"Xiao","year":"2023","journal-title":"J Med Chem"},{"key":"10.1016\/j.gde.2024.102230_bib27","article-title":"Structure-based design of ligands of the m6A-RNA reader YTHDC1","volume":"5","author":"Li","year":"2022","journal-title":"Eur J Med Chem Rep"},{"key":"10.1016\/j.gde.2024.102230_bib28","doi-asserted-by":"crossref","first-page":"1500","DOI":"10.1021\/acsmedchemlett.2c00303","article-title":"Fragment Ligands of the m6A-RNA reader YTHDF2","volume":"13","author":"Nai","year":"2022","journal-title":"ACS Med Chem Lett"},{"key":"10.1016\/j.gde.2024.102230_bib29","doi-asserted-by":"crossref","first-page":"872","DOI":"10.1021\/acsptsci.2c00008","article-title":"Small-molecule ebselen binds to YTHDF proteins interfering with the recognition of N 6-methyladenosine-modified RNAs","volume":"5","author":"Micaelli","year":"2022","journal-title":"ACS Pharm Transl Sci"},{"key":"10.1016\/j.gde.2024.102230_sbref28","doi-asserted-by":"crossref","first-page":"1294","DOI":"10.1016\/j.ccell.2023.04.019","article-title":"YTHDF2 inhibition potentiates radiotherapy antitumor efficacy","volume":"41","author":"Wang","year":"2023","journal-title":"Cancer Cell"},{"key":"10.1016\/j.gde.2024.102230_bib31","doi-asserted-by":"crossref","first-page":"845","DOI":"10.1158\/0008-5472.CAN-21-4249","article-title":"The RNA m6A reader YTHDF1 is required for acute myeloid leukemia progression","volume":"83","author":"Hong","year":"2023","journal-title":"Cancer Res"},{"key":"10.1016\/j.gde.2024.102230_bib32","article-title":"Discovery of a selective YTHDC1 inhibitor that targets acute myeloid leukemia","author":"Yang","year":"2023","journal-title":"Research Square"},{"key":"10.1016\/j.gde.2024.102230_bib33","doi-asserted-by":"crossref","first-page":"777","DOI":"10.1021\/acsmedchemlett.3c00062","article-title":"Covalent S-adenosylhomocysteine-based DNA methyltransferase 2 inhibitors with a new type of Aryl Warhead","volume":"14","author":"Schwickert","year":"2023","journal-title":"ACS Med Chem Lett"},{"key":"10.1016\/j.gde.2024.102230_bib34","doi-asserted-by":"crossref","DOI":"10.1002\/anie.202311924","article-title":"Chemical proteomic discovery of isotype-selective covalent inhibitors of the RNA methyltransferase NSUN2","volume":"62","author":"Tao","year":"2023","journal-title":"Angew Chem Int Ed Engl"},{"key":"10.1016\/j.gde.2024.102230_bib35","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1021\/acsbiomedchemau.3c00030","article-title":"Small-molecule inhibitors of the m7G-RNA writer METTL1","volume":"4","author":"Nai","year":"2024","journal-title":"ACS Bio Med Chem Au"},{"key":"10.1016\/j.gde.2024.102230_bib36","article-title":"AVA-ADR-001 suppresses tumor growth and induces anti-tumor immunity by selectively inhibiting ADAR1 p150","author":"Kulkarni","year":"2023","journal-title":"Res Sq"},{"key":"10.1016\/j.gde.2024.102230_sbref35","doi-asserted-by":"crossref","first-page":"932","DOI":"10.1038\/s43018-021-00238-0","article-title":"Targeting PUS7 suppresses tRNA pseudouridylation and glioblastoma tumorigenesis","volume":"2","author":"Cui","year":"2021","journal-title":"Nat Cancer"},{"key":"10.1016\/j.gde.2024.102230_bib38","doi-asserted-by":"crossref","first-page":"20159","DOI":"10.1073\/pnas.1918986117","article-title":"ALKBH5 regulates anti-PD-1 therapy response by modulating lactate and suppressive immune cell accumulation in tumor microenvironment","volume":"117","author":"Li","year":"2020","journal-title":"Proc Natl Acad Sci USA"},{"key":"10.1016\/j.gde.2024.102230_sbref37","doi-asserted-by":"crossref","first-page":"15944","DOI":"10.1021\/acs.jmedchem.3c01374","article-title":"Discovery of pyrazolo[1,5-a]pyrimidine derivative as a novel and selective ALKBH5 inhibitor for the treatment of AML","volume":"66","author":"Wang","year":"2023","journal-title":"J Med Chem"},{"key":"10.1016\/j.gde.2024.102230_bib40","doi-asserted-by":"crossref","first-page":"4304","DOI":"10.1016\/j.molcel.2023.10.028","article-title":"FMRP phosphorylation modulates neuronal translation through YTHDF1","volume":"83","author":"Zou","year":"2023","journal-title":"Mol Cell"},{"key":"10.1016\/j.gde.2024.102230_bib41","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1038\/s41573-021-00371-6","article-title":"PROTAC targeted protein degraders: the past is prologue","volume":"21","author":"B\u00e9k\u00e9s","year":"2022","journal-title":"Nat Rev Drug Discov"},{"key":"10.1016\/j.gde.2024.102230_bib42","doi-asserted-by":"crossref","first-page":"713","DOI":"10.1021\/jacsau.4c00040","article-title":"Proteolysis targeting chimera degraders of the METTL3-14 m6A-RNA methyltransferase","volume":"4","author":"Errani","year":"2024","journal-title":"JACS Au"},{"key":"10.1016\/j.gde.2024.102230_sbref41","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1016\/j.chembiol.2023.12.009","article-title":"Discovery of a PROTAC degrader for METTL3-METTL14 complex","volume":"31","author":"Du","year":"2024","journal-title":"Cell Chem Biol"},{"key":"10.1016\/j.gde.2024.102230_bib44","doi-asserted-by":"crossref","first-page":"1019","DOI":"10.1126\/science.aaq0180","article-title":"RNA editing with CRISPR-Cas13","volume":"358","author":"Cox","year":"2017","journal-title":"Science"},{"key":"10.1016\/j.gde.2024.102230_bib45","doi-asserted-by":"crossref","first-page":"1431","DOI":"10.1038\/s41587-020-0572-6","article-title":"Programmable m6A modification of cellular RNAs with a Cas13-directed methyltransferase","volume":"38","author":"Wilson","year":"2020","journal-title":"Nat Biotechnol"},{"key":"10.1016\/j.gde.2024.102230_bib46","doi-asserted-by":"crossref","first-page":"5684","DOI":"10.1093\/nar\/gkaa269","article-title":"Targeted mRNA demethylation using an engineered dCas13b-ALKBH5 fusion protein","volume":"48","author":"Li","year":"2020","journal-title":"Nucleic Acids Res"},{"key":"10.1016\/j.gde.2024.102230_bib47","doi-asserted-by":"crossref","DOI":"10.1186\/s12943-020-01289-0","article-title":"Programmable N6-methyladenosine modification of CDCP1 mRNA by RCas9-methyltransferase like 3 conjugates promotes bladder cancer development","volume":"19","author":"Ying","year":"2020","journal-title":"Mol Cancer"},{"key":"10.1016\/j.gde.2024.102230_bib48","doi-asserted-by":"crossref","first-page":"1311","DOI":"10.1261\/rna.070706.119","article-title":"Sequence-specific m6A demethylation in RNA by FTO fused to RCas9","volume":"25","author":"Rau","year":"2019","journal-title":"RNA"},{"key":"10.1016\/j.gde.2024.102230_bib49","doi-asserted-by":"crossref","first-page":"865","DOI":"10.1038\/s41589-019-0327-1","article-title":"Programmable RNA N6-methyladenosine editing by CRISPR-Cas9 conjugates","volume":"15","author":"Liu","year":"2019","journal-title":"Nat Chem Biol"},{"key":"10.1016\/j.gde.2024.102230_bib50","article-title":"Inducible and reversible RNA N6-methyladenosine editing","volume":"13","author":"Shi","year":"2022","journal-title":"Nat Commun"},{"key":"10.1016\/j.gde.2024.102230_bib51","doi-asserted-by":"crossref","first-page":"7361","DOI":"10.1093\/nar\/gkab517","article-title":"Epitranscriptomic editing of the RNA N6-methyladenosine modification by dCasRx conjugated methyltransferase and demethylase","volume":"49","author":"Xia","year":"2021","journal-title":"Nucleic Acids Res"},{"key":"10.1016\/j.gde.2024.102230_bib52","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1016\/j.molcel.2023.01.009","article-title":"Targeted pseudouridylation: an approach for suppressing nonsense mutations in disease genes","volume":"83","author":"Adachi","year":"2023","journal-title":"Mol Cell"},{"key":"10.1016\/j.gde.2024.102230_sbref51","doi-asserted-by":"crossref","first-page":"938","DOI":"10.1038\/s41587-021-01171-4","article-title":"Efficient in vitro and in vivo RNA editing via recruitment of endogenous ADARs using circular guide RNAs","volume":"40","author":"Katrekar","year":"2022","journal-title":"Nat Biotechnol"},{"key":"10.1016\/j.gde.2024.102230_bib54","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1016\/j.molcel.2022.11.011","article-title":"CRISPR-free, programmable RNA pseudouridylation to suppress premature termination codons","volume":"83","author":"Song","year":"2023","journal-title":"Mol Cell"},{"key":"10.1016\/j.gde.2024.102230_bib55","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1016\/j.tips.2023.11.002","article-title":"The rise of epitranscriptomics: recent developments and future directions","volume":"45","author":"Cerneckis","year":"2024","journal-title":"Trends Pharm Sci"},{"key":"10.1016\/j.gde.2024.102230_bib56","unstructured":"A Sapetschnig et al., abstract 105P, ESMO Targeted Anticancer Therapies Congress, Paris, February 2024."}],"container-title":["Current Opinion in Genetics &amp; Development"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0959437X24000790?httpAccept=text\/xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0959437X24000790?httpAccept=text\/plain","content-type":"text\/plain","content-version":"vor","intended-application":"text-mining"}],"deposited":{"date-parts":[[2024,10,9]],"date-time":"2024-10-09T01:52:19Z","timestamp":1728438739000},"score":1,"resource":{"primary":{"URL":"https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S0959437X24000790"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,8]]},"references-count":56,"alternative-id":["S0959437X24000790"],"URL":"https:\/\/doi.org\/10.1016\/j.gde.2024.102230","relation":{},"ISSN":["0959-437X"],"issn-type":[{"value":"0959-437X","type":"print"}],"subject":[],"published":{"date-parts":[[2024,8]]},"assertion":[{"value":"Elsevier","name":"publisher","label":"This article is maintained by"},{"value":"Therapeutic strategies to target the epitranscriptomic machinery","name":"articletitle","label":"Article Title"},{"value":"Current Opinion in Genetics & Development","name":"journaltitle","label":"Journal Title"},{"value":"https:\/\/doi.org\/10.1016\/j.gde.2024.102230","name":"articlelink","label":"CrossRef DOI link to publisher maintained version"},{"value":"article","name":"content_type","label":"Content Type"},{"value":"\u00a9 2024 The Authors. Published by Elsevier Ltd.","name":"copyright","label":"Copyright"}],"article-number":"102230"}}