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Discovery of the 4-...
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Parenti, Marco DanielePhotoreact Natl Res Council, Inst Organ Synth, I-40129 Bologna, Italy.,Institute of Organic Synthesis and Photoreactivity (CNR-ISOF)
(författare)
Discovery of the 4-aminopiperidine-based compound EM127 for the site-specific covalent inhibition of SMYD3
- Artikel/kapitelEngelska2022
Förlag, utgivningsår, omfång ...
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Elsevier,2022
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printrdacarrier
Nummerbeteckningar
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LIBRIS-ID:oai:DiVA.org:uu-487227
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https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-487227URI
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https://doi.org/10.1016/j.ejmech.2022.114683DOI
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https://lup.lub.lu.se/record/69e4fd04-a282-449a-bcd5-b9e41ddefc1aURI
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Språk:engelska
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Sammanfattning på:engelska
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Ämneskategori:ref swepub-contenttype
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Ämneskategori:art swepub-publicationtype
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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.
Ämnesord och genrebeteckningar
Biuppslag (personer, institutioner, konferenser, titlar ...)
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Naldi, MarinaAlma Mater Studiorum Univ Bologna, Dept Pharm & Biotechnol, Bologna, Italy.;Univ Bologna, Ctr Appl Biomed Res, Bologna, Italy.,University of Bologna
(författare)
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Manoni, ElisabettaPhotoreact Natl Res Council, Inst Organ Synth, I-40129 Bologna, Italy.,Institute of Organic Synthesis and Photoreactivity (CNR-ISOF)
(författare)
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Fabini, EdoardoAlma Mater Studiorum Univ Bologna, Dept Pharm & Biotechnol, Bologna, Italy.,University of Bologna
(författare)
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Cederfelt, DanielaUppsala University,Uppsala universitet,Biokemi(Swepub:uu)daner857
(författare)
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Talibov, Vladimir O,1991-Uppsala University,Lund University,Lunds universitet,Uppsala universitet,Biokemi,BioMAX beam line, MAX IV Lab, Lund 22484, Sweden.,MAX IV-laboratoriet,MAX IV Laboratory(Swepub:lu)vl0233ta
(författare)
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Gressani, ValeriaUniv Milan, Dept Biosci, I-20133 Milan, Italy.,University of Milan
(författare)
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Guven, UmmuUniv Milan, Dept Biosci, I-20133 Milan, Italy.,University of Milan
(författare)
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Grossi, ValentinaIRCCSS Bellis Res Hosp, Med Genet Natl Inst Gastroenterol, Castellana Grotte, Italy.,Hospital Saverio De Bellis
(författare)
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Fasano, CandidaIRCCSS Bellis Res Hosp, Med Genet Natl Inst Gastroenterol, Castellana Grotte, Italy.,Hospital Saverio De Bellis
(författare)
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Sanese, PaolaIRCCSS Bellis Res Hosp, Med Genet Natl Inst Gastroenterol, Castellana Grotte, Italy.,Hospital Saverio De Bellis
(författare)
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De Marco, KatiaIRCCSS Bellis Res Hosp, Med Genet Natl Inst Gastroenterol, Castellana Grotte, Italy.,Hospital Saverio De Bellis
(författare)
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Shtil, Alexander A.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
(författare)
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V. Kurkin, AlexanderLomonosov Moscow State Univ, Dept Chem, Moscow 119991, Russia.,Lomonosov Moscow State University
(författare)
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Altieri, AndreaLomonosov Moscow State Univ, Dept Chem, Moscow 119991, Russia.;EDASA Sci Srls, I-66050 San Salvo, CH, Italy.
(författare)
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Danielson, U. Helena,Professor,1959-Uppsala University,Uppsala universitet,Biokemi,Science for Life Laboratory, SciLifeLab(Swepub:uu)helenads
(författare)
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Caretti, GiuseppinaUniv Milan, Dept Biosci, I-20133 Milan, Italy.,University of Milan
(författare)
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Simone, CristianoIRCCSS 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
(författare)
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Varchi, GretaPhotoreact Natl Res Council, Inst Organ Synth, I-40129 Bologna, Italy.,Institute of Organic Synthesis and Photoreactivity (CNR-ISOF)
(författare)
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Bartolini, ManuelaAlma Mater Studiorum Univ Bologna, Dept Pharm & Biotechnol, Bologna, Italy.,University of Bologna
(författare)
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Del Rio, AlbertoPhotoreact 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)
(författare)
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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)
Sammanhörande titlar
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Ingår i:European Journal of Medicinal Chemistry: Elsevier2430223-52341768-3254
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- Av författaren/redakt...
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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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visa fler...
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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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