{"entity": "publication", "iuid": "a0af0f79193b46568ba7ed96cd1ee69a", "timestamp": "2026-08-22T06:56:35.961Z", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/a0af0f79193b46568ba7ed96cd1ee69a.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/a0af0f79193b46568ba7ed96cd1ee69a"}}, "title": "Discovery of the 4-aminopiperidine-based compound EM127 for the site-specific covalent inhibition of SMYD3.", "authors": [{"family": "Parenti", "given": "Marco Daniele", "initials": "MD"}, {"family": "Naldi", "given": "Marina", "initials": "M"}, {"family": "Manoni", "given": "Elisabetta", "initials": "E"}, {"family": "Fabini", "given": "Edoardo", "initials": "E"}, {"family": "Cederfelt", "given": "Daniela", "initials": "D"}, {"family": "Talibov", "given": "Vladimir O", "initials": "VO"}, {"family": "Gressani", "given": "Valeria", "initials": "V"}, {"family": "Guven", "given": "Ummu", "initials": "U"}, {"family": "Grossi", "given": "Valentina", "initials": "V"}, {"family": "Fasano", "given": "Candida", "initials": "C"}, {"family": "Sanese", "given": "Paola", "initials": "P"}, {"family": "De Marco", "given": "Katia", "initials": "K"}, {"family": "Shtil", "given": "Alexander A", "initials": "AA"}, {"family": "Kurkin", "given": "Alexander V", "initials": "AV"}, {"family": "Altieri", "given": "Andrea", "initials": "A"}, {"family": "Danielson", "given": "U Helena", "initials": "UH"}, {"family": "Caretti", "given": "Giuseppina", "initials": "G"}, {"family": "Simone", "given": "Cristiano", "initials": "C"}, {"family": "Varchi", "given": "Greta", "initials": "G"}, {"family": "Bartolini", "given": "Manuela", "initials": "M"}, {"family": "Del Rio", "given": "Alberto", "initials": "A"}], "type": "journal article", "published": "2022-12-05", "journal": {"title": "Eur J Med Chem", "issn": "1768-3254", "volume": "243", "pages": "114683", "issn-l": "0223-5234"}, "abstract": "Recent findings support the hypothesis that inhibition of SMYD3 methyltransferase may be a therapeutic avenue for some of the deadliest cancer types. Herein, active site-selective covalent SMYD3 inhibitors were designed by introducing an appropriate reactive cysteine trap into reversible first-generation SMYD3 inhibitors. The 4-aminopiperidine derivative EM127 (11C) bearing a 2-chloroethanoyl group as reactive warhead showed selectivity for Cys186, located in the substrate/histone binding pocket. Selectivity towards Cys186 was retained even at high inhibitor/enzyme ratio, as shown by mass spectrometry. The mode of interaction with the SMYD3 substrate/histone binding pocket was revealed by crystallographic studies. In enzymatic assays, 11C showed a stronger SMYD3 inhibitory effect compared to the reference inhibitor EPZ031686. Remarkably, 11C attenuated the proliferation of MDA-MB-231 breast cancer cell line at the same low micromolar range of concentrations that reduced SMYD3 mediated ERK signaling in HCT116 colorectal cancer and MDA-MB-231 breast cancer cells. Furthermore, 11C (5 \u03bcM) strongly decreased the steady-state mRNA levels of genes important for tumor biology such as cyclin dependent kinase 2, c-MET, N-cadherin and fibronectin 1, all known to be regulated, at least in part, by SMYD3. Thus, 11C is as a first example of second generation SMYD3 inhibitors; this agent represents a covalent and a site specific SMYD3 binder capable of potent and prolonged attenuation of methyltransferase activity.", "doi": "10.1016/j.ejmech.2022.114683", "pmid": "36116234", "labels": [], "xrefs": [{"db": "pii", "key": "S0223-5234(22)00585-2"}], "notes": [], "created": "2026-08-20T07:54:41.104Z", "modified": "2026-08-20T07:54:41.144Z"}