![\"\"](\"https:\/\/sites.unica.it\/pe2026\/files\/2026\/05\/emanuele_fabbrizi.png\")
<\/figure>OC26 – Emanuele Fabbrizi<\/strong><\/p>\n\n\n\n Department of Drug Chemistry and Technologies, Sapienza University of Rome, Italy<\/p>\n\n\n\n e-mail<\/a> –<\/strong> ORCID<\/a><\/strong><\/p>\n<\/div><\/div>\n\n\n\n <\/p>\n\n\n\n <\/p>\n","protected":false},"excerpt":{"rendered":" OC26 – Emanuele Fabbrizi Department of Drug Chemistry and Technologies, Sapienza University of Rome, Italy e-mail – ORCID Targeting m6A Epitranscriptomic Machinery: Design and Biological Characterization of Potent Quinazoline-Derived METTL3\u2013METTL14 Inhibitors Fabbrizi Emanuele1,\u00a0Fiorentino Francesco\u00a02,\u00a0Mancini Andrea1, Caflisch […]<\/p>\n","protected":false},"author":9643,"featured_media":0,"comment_status":"closed","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[1],"tags":[],"class_list":["post-1707","post","type-post","status-publish","format-standard","hentry","category-senza-categoria"],"_links":{"self":[{"href":"https:\/\/sites.unica.it\/pe2026\/wp-json\/wp\/v2\/posts\/1707","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/sites.unica.it\/pe2026\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/sites.unica.it\/pe2026\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/sites.unica.it\/pe2026\/wp-json\/wp\/v2\/users\/9643"}],"replies":[{"embeddable":true,"href":"https:\/\/sites.unica.it\/pe2026\/wp-json\/wp\/v2\/comments?post=1707"}],"version-history":[{"count":8,"href":"https:\/\/sites.unica.it\/pe2026\/wp-json\/wp\/v2\/posts\/1707\/revisions"}],"predecessor-version":[{"id":1826,"href":"https:\/\/sites.unica.it\/pe2026\/wp-json\/wp\/v2\/posts\/1707\/revisions\/1826"}],"wp:attachment":[{"href":"https:\/\/sites.unica.it\/pe2026\/wp-json\/wp\/v2\/media?parent=1707"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/sites.unica.it\/pe2026\/wp-json\/wp\/v2\/categories?post=1707"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/sites.unica.it\/pe2026\/wp-json\/wp\/v2\/tags?post=1707"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}Targeting m6A Epitranscriptomic Machinery: Design and Biological Characterization of Potent Quinazoline-Derived METTL3\u2013METTL14 Inhibitors<\/strong><\/strong><\/strong><\/td><\/tr> Fabbrizi Emanuele1<\/sup>,\u00a0Fiorentino Francesco\u00a02<\/sup>,\u00a0Mancini Andrea1<\/sup>, Caflisch Amedeo3<\/sup>, Fatica Alessandro2<\/sup>, Rotili Dante4<\/sup>,\u00a0and\u00a0Antonello Mai1<\/sup>
<\/em>
1<\/sup><\/em> Department of Drug Chemistry and Technologies, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy;\u00a0\u00a0
2<\/sup><\/em> Department of Biochemical Sciences, Sapienza University of Rome, 00185 Rome,\u00a0Italy;\u00a0
3<\/sup><\/em> Department of Biochemistry, University of Zurich, Zurich,\u00a0Switzerland;\u00a0
4<\/sup><\/em> Department of Science, Roma Tre University, 00146 Rome, Italy.\u00a0<\/td><\/tr>Abstract<\/strong>
Epitranscriptomics involves dynamic, reversible RNA modifications regulating splicing, nuclear export, stability, and translation without altering sequence. N6-methyladenosine (m6A) is the most abundant internal modification in eukaryotic mRNA and is installed by a multicomponent methyltransferase complex whose catalytic core is the METTL3\/METTL14 heterodimer [1]. METTL3 contains the SAM-dependent catalytic domain with the conserved DPPW motif, whereas METTL14 acts as an RNA-binding scaffold enabling substrate recognition and positioning [2]. Dysregulation of this complex promotes tumorigenesis by enhancing stability and translation of oncogenic transcripts such as c-MYC, supporting malignant growth, thus representing a therapeutic target [3]. We report the design, synthesis, and biochemical characterization of 30 non-nucleosidic quinazoline derivatives as METTL3\/METTL14 inhibitors. The quinazoline scaffold mimics adenine interactions in the catalytic pocket and enables SAR exploration via substitutions at C2, C4, C6, and C7. Orthogonal biochemical assays identified sub-micromolar inhibitors. In HTRF assays, IC50<\/sub> values ranged from 120 to 740 nM, with MC4774<\/strong> as the most potent (119 nM). In the HotSpot radiometric assay ([\u00b3H]-SAM incorporation), potency increased markedly: MC4905<\/strong> (1.56 nM), MC4118<\/strong> (1.86 nM), MC4009<\/strong> (2.15 nM), and MC4774<\/strong> (2.22 nM) (Figure 1). Compounds showed >1000-fold selectivity over EZH2, G9a, PRMT1, and SET8, with no inhibition up to 10 \u00b5M.
Cell assays showed a favorable therapeutic index: MC4905<\/strong> and MC4009<\/strong> preserved viability in CD34\u207a cells (88\u201392%) and MCF10A cells (85\u201390%), while reducing MDA-MB-231 viability to ~25\u201330% at 5 \u00b5M (72 h), outperforming STM2457 [3]. Combination with cisplatin or olaparib enhanced antiproliferative effects. In MOLM-13 AML cells, IC50<\/sub> values were 1.47 and 1.59 \u00b5M, with 55\u201365% m6A reduction and ~65% c-MYC downregulation, confirming on-target activity. <\/td><\/tr>References <\/strong>
[1] Saletore Y, Meyer K, Korlach J, Vilfan ID, Jaffrey S, Mason CE. The birth of the Epitranscriptome: deciphering the function of RNA modifications. Genome Biol. 2012 Oct 31;13(10):175.
[2] Wang X, Feng J, Xue Y, Guan Z, Zhang D, Liu Z, Gong Z, Wang Q, Huang J, Tang C, Zou T, Yin P. Structural basis of N(6)-adenosine methylation by the METTL3-METTL14 complex. Nature. 2016 Jun 23;534(7608):575-8.
[3] Fiorentino F, Menna M, Rotili D, Valente S, Mai A. METTL3 from Target Validation to the First Small-Molecule Inhibitors: A Medicinal Chemistry Journey. J Med Chem. 2023 Feb 9;66(3):1654-1677. doi: 10.1021\/acs.jmedchem.2c01601. Epub 2023 Jan 24. PMID: 36692498; PMCID: PMC9923689. <\/td><\/tr><\/tbody><\/table><\/div><\/figure>\n\n\n\n