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Sökning: WFRF:(Shtil Alexander A.) > (2022) > Discovery of the 4-...

  • 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 ...

  • Elsevier,2022
  • printrdacarrier

Nummerbeteckningar

  • LIBRIS-ID:oai:DiVA.org:uu-487227
  • https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-487227URI
  • https://doi.org/10.1016/j.ejmech.2022.114683DOI
  • https://lup.lub.lu.se/record/69e4fd04-a282-449a-bcd5-b9e41ddefc1aURI

Kompletterande språkuppgifter

  • Språk:engelska
  • Sammanfattning på:engelska

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Klassifikation

  • Ämneskategori:ref swepub-contenttype
  • Ämneskategori:art swepub-publicationtype

Anmärkningar

  • 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 ...)

  • Naldi, MarinaAlma Mater Studiorum Univ Bologna, Dept Pharm & Biotechnol, Bologna, Italy.;Univ Bologna, Ctr Appl Biomed Res, Bologna, Italy.,University of Bologna (författare)
  • Manoni, ElisabettaPhotoreact Natl Res Council, Inst Organ Synth, I-40129 Bologna, Italy.,Institute of Organic Synthesis and Photoreactivity (CNR-ISOF) (författare)
  • Fabini, EdoardoAlma Mater Studiorum Univ Bologna, Dept Pharm & Biotechnol, Bologna, Italy.,University of Bologna (författare)
  • Cederfelt, DanielaUppsala University,Uppsala universitet,Biokemi(Swepub:uu)daner857 (författare)
  • 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)
  • Gressani, ValeriaUniv Milan, Dept Biosci, I-20133 Milan, Italy.,University of Milan (författare)
  • Guven, UmmuUniv Milan, Dept Biosci, I-20133 Milan, Italy.,University of Milan (författare)
  • Grossi, ValentinaIRCCSS Bellis Res Hosp, Med Genet Natl Inst Gastroenterol, Castellana Grotte, Italy.,Hospital Saverio De Bellis (författare)
  • Fasano, CandidaIRCCSS Bellis Res Hosp, Med Genet Natl Inst Gastroenterol, Castellana Grotte, Italy.,Hospital Saverio De Bellis (författare)
  • Sanese, PaolaIRCCSS Bellis Res Hosp, Med Genet Natl Inst Gastroenterol, Castellana Grotte, Italy.,Hospital Saverio De Bellis (författare)
  • De Marco, KatiaIRCCSS Bellis Res Hosp, Med Genet Natl Inst Gastroenterol, Castellana Grotte, Italy.,Hospital Saverio De Bellis (författare)
  • 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)
  • V. Kurkin, AlexanderLomonosov Moscow State Univ, Dept Chem, Moscow 119991, Russia.,Lomonosov Moscow State University (författare)
  • Altieri, AndreaLomonosov Moscow State Univ, Dept Chem, Moscow 119991, Russia.;EDASA Sci Srls, I-66050 San Salvo, CH, Italy. (författare)
  • Danielson, U. Helena,Professor,1959-Uppsala University,Uppsala universitet,Biokemi,Science for Life Laboratory, SciLifeLab(Swepub:uu)helenads (författare)
  • Caretti, GiuseppinaUniv Milan, Dept Biosci, I-20133 Milan, Italy.,University of Milan (författare)
  • 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)
  • Varchi, GretaPhotoreact Natl Res Council, Inst Organ Synth, I-40129 Bologna, Italy.,Institute of Organic Synthesis and Photoreactivity (CNR-ISOF) (författare)
  • Bartolini, ManuelaAlma Mater Studiorum Univ Bologna, Dept Pharm & Biotechnol, Bologna, Italy.,University of Bologna (författare)
  • 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)
  • 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

  • Ingår i:European Journal of Medicinal Chemistry: Elsevier2430223-52341768-3254

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