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Discovery of the 4-...
Discovery of the 4-aminopiperidine-based compound EM127 for the site-specific covalent inhibition of SMYD3
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- Parenti, Marco Daniele (author)
- Photoreact Natl Res Council, Inst Organ Synth, I-40129 Bologna, Italy.,Institute of Organic Synthesis and Photoreactivity (CNR-ISOF)
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- Naldi, Marina (author)
- Alma Mater Studiorum Univ Bologna, Dept Pharm & Biotechnol, Bologna, Italy.;Univ Bologna, Ctr Appl Biomed Res, Bologna, Italy.,University of Bologna
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- Manoni, Elisabetta (author)
- Photoreact Natl Res Council, Inst Organ Synth, I-40129 Bologna, Italy.,Institute of Organic Synthesis and Photoreactivity (CNR-ISOF)
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- Fabini, Edoardo (author)
- Alma Mater Studiorum Univ Bologna, Dept Pharm & Biotechnol, Bologna, Italy.,University of Bologna
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- Cederfelt, Daniela (author)
- Uppsala University,Uppsala universitet,Biokemi
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- Talibov, Vladimir O, 1991- (author)
- Uppsala University,Lund University,Lunds universitet,Uppsala universitet,Biokemi,BioMAX beam line, MAX IV Lab, Lund 22484, Sweden.,MAX IV-laboratoriet,MAX IV Laboratory
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- Gressani, Valeria (author)
- Univ Milan, Dept Biosci, I-20133 Milan, Italy.,University of Milan
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- Guven, Ummu (author)
- Univ Milan, Dept Biosci, I-20133 Milan, Italy.,University of Milan
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- Grossi, Valentina (author)
- IRCCSS Bellis Res Hosp, Med Genet Natl Inst Gastroenterol, Castellana Grotte, Italy.,Hospital Saverio De Bellis
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- Fasano, Candida (author)
- IRCCSS Bellis Res Hosp, Med Genet Natl Inst Gastroenterol, Castellana Grotte, Italy.,Hospital Saverio De Bellis
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- Sanese, Paola (author)
- IRCCSS Bellis Res Hosp, Med Genet Natl Inst Gastroenterol, Castellana Grotte, Italy.,Hospital Saverio De Bellis
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- De Marco, Katia (author)
- IRCCSS Bellis Res Hosp, Med Genet Natl Inst Gastroenterol, Castellana Grotte, Italy.,Hospital Saverio De Bellis
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- Shtil, Alexander A. (author)
- Lomonosov Moscow State Univ, Dept Chem, Moscow 119991, Russia.;Blokhin Natl Med Res Ctr Oncol, Moscow 115478, Russia.,Lomonosov Moscow State University,N.N. Blokhin Russian Cancer Research Center, Russian Academy of Medical Sciences,EDASA Scientific Srls
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- V. Kurkin, Alexander (author)
- Lomonosov Moscow State Univ, Dept Chem, Moscow 119991, Russia.,Lomonosov Moscow State University
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- Altieri, Andrea (author)
- Lomonosov Moscow State Univ, Dept Chem, Moscow 119991, Russia.;EDASA Sci Srls, I-66050 San Salvo, CH, Italy.
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- Danielson, U. Helena, Professor, 1959- (author)
- Uppsala University,Uppsala universitet,Biokemi,Science for Life Laboratory, SciLifeLab
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- Caretti, Giuseppina (author)
- Univ Milan, Dept Biosci, I-20133 Milan, Italy.,University of Milan
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- Simone, Cristiano (author)
- IRCCSS Bellis Res Hosp, Med Genet Natl Inst Gastroenterol, Castellana Grotte, Italy.;Univ Bari Aldo Moro, Dept Biomed Sci & Human Oncol DIMO, Med Genet, I-70124 Bari, Italy.,University of Bari Aldo Moro,Hospital Saverio De Bellis
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- Varchi, Greta (author)
- Photoreact Natl Res Council, Inst Organ Synth, I-40129 Bologna, Italy.,Institute of Organic Synthesis and Photoreactivity (CNR-ISOF)
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- Bartolini, Manuela (author)
- Alma Mater Studiorum Univ Bologna, Dept Pharm & Biotechnol, Bologna, Italy.,University of Bologna
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- Del Rio, Alberto (author)
- Photoreact Natl Res Council, Inst Organ Synth, I-40129 Bologna, Italy.;Innovamol Consulting Srl, Via San Faustino 167, I-41126 Modena, Italy.,Institute of Organic Synthesis and Photoreactivity (CNR-ISOF)
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Photoreact Natl Res Council, Inst Organ Synth, I-40129 Bologna, Italy Institute of Organic Synthesis and Photoreactivity (CNR-ISOF) (creator_code:org_t)
- Elsevier, 2022
- 2022
- English.
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In: European Journal of Medicinal Chemistry. - : Elsevier. - 0223-5234 .- 1768-3254. ; 243
- Related links:
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http://dx.doi.org/10...
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https://urn.kb.se/re...
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Abstract
Subject headings
Close
- 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-amino-piperidine 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 mu M) 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.
Subject headings
- NATURVETENSKAP -- Biologi -- Biokemi och molekylärbiologi (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences -- Biochemistry and Molecular Biology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Läkemedelskemi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Medicinal Chemistry (hsv//eng)
Keyword
- Covalent inhibitor
- SMYD3
- Lysine methyltransferase
- Epigenetic inhibitors
- Cancer target therapy
- Cancer target therapy
- Covalent inhibitor
- Epigenetic inhibitors
- Lysine methyltransferase
- SMYD3
Publication and Content Type
- ref (subject category)
- art (subject category)
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Parenti, Marco D ...
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Naldi, Marina
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Manoni, Elisabet ...
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Fabini, Edoardo
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Cederfelt, Danie ...
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Talibov, Vladimi ...
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Gressani, Valeri ...
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Guven, Ummu
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Grossi, Valentin ...
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Fasano, Candida
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Sanese, Paola
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De Marco, Katia
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Shtil, Alexander ...
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V. Kurkin, Alexa ...
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Altieri, Andrea
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Danielson, U. He ...
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Caretti, Giusepp ...
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Simone, Cristian ...
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Varchi, Greta
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Bartolini, Manue ...
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Del Rio, Alberto
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- NATURAL SCIENCES
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NATURAL SCIENCES
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and Biological Scien ...
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and Biochemistry and ...
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Medicinal Chemis ...
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European Journal ...
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Uppsala University
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Lund University