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Sökning: id:"swepub:oai:DiVA.org:uu-487227" > Discovery of the 4-...

Discovery of the 4-aminopiperidine-based compound EM127 for the site-specific covalent inhibition of SMYD3

Parenti, Marco Daniele (författare)
Photoreact Natl Res Council, Inst Organ Synth, I-40129 Bologna, Italy.,Institute of Organic Synthesis and Photoreactivity (CNR-ISOF)
Naldi, Marina (författare)
Alma Mater Studiorum Univ Bologna, Dept Pharm & Biotechnol, Bologna, Italy.;Univ Bologna, Ctr Appl Biomed Res, Bologna, Italy.,University of Bologna
Manoni, Elisabetta (författare)
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 (författare)
Alma Mater Studiorum Univ Bologna, Dept Pharm & Biotechnol, Bologna, Italy.,University of Bologna
Cederfelt, Daniela (författare)
Uppsala University,Uppsala universitet,Biokemi
Talibov, Vladimir O, 1991- (författare)
Uppsala University,Lund University,Lunds universitet,Uppsala universitet,Biokemi,BioMAX beam line, MAX IV Lab, Lund 22484, Sweden.,MAX IV-laboratoriet,MAX IV Laboratory
Gressani, Valeria (författare)
Univ Milan, Dept Biosci, I-20133 Milan, Italy.,University of Milan
Guven, Ummu (författare)
Univ Milan, Dept Biosci, I-20133 Milan, Italy.,University of Milan
Grossi, Valentina (författare)
IRCCSS Bellis Res Hosp, Med Genet Natl Inst Gastroenterol, Castellana Grotte, Italy.,Hospital Saverio De Bellis
Fasano, Candida (författare)
IRCCSS Bellis Res Hosp, Med Genet Natl Inst Gastroenterol, Castellana Grotte, Italy.,Hospital Saverio De Bellis
Sanese, Paola (författare)
IRCCSS Bellis Res Hosp, Med Genet Natl Inst Gastroenterol, Castellana Grotte, Italy.,Hospital Saverio De Bellis
De Marco, Katia (författare)
IRCCSS Bellis Res Hosp, Med Genet Natl Inst Gastroenterol, Castellana Grotte, Italy.,Hospital Saverio De Bellis
Shtil, Alexander A. (författare)
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
V. Kurkin, Alexander (författare)
Lomonosov Moscow State Univ, Dept Chem, Moscow 119991, Russia.,Lomonosov Moscow State University
Altieri, Andrea (författare)
Lomonosov Moscow State Univ, Dept Chem, Moscow 119991, Russia.;EDASA Sci Srls, I-66050 San Salvo, CH, Italy.
Danielson, U. Helena, Professor, 1959- (författare)
Uppsala University,Uppsala universitet,Biokemi,Science for Life Laboratory, SciLifeLab
Caretti, Giuseppina (författare)
Univ Milan, Dept Biosci, I-20133 Milan, Italy.,University of Milan
Simone, Cristiano (författare)
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
Varchi, Greta (författare)
Photoreact Natl Res Council, Inst Organ Synth, I-40129 Bologna, Italy.,Institute of Organic Synthesis and Photoreactivity (CNR-ISOF)
Bartolini, Manuela (författare)
Alma Mater Studiorum Univ Bologna, Dept Pharm & Biotechnol, Bologna, Italy.,University of Bologna
Del Rio, Alberto (författare)
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
Engelska.
Ingår i: European Journal of Medicinal Chemistry. - : Elsevier. - 0223-5234 .- 1768-3254. ; 243
Relaterad länk:
http://dx.doi.org/10...
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https://urn.kb.se/re...
https://doi.org/10.1...
https://lup.lub.lu.s...
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  • Tidskriftsartikel (refereegranskat)
Abstract Ämnesord
Stäng  
  • 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

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)

Nyckelord

Covalent inhibitor
SMYD3
Lysine methyltransferase
Epigenetic inhibitors
Cancer target therapy
Cancer target therapy
Covalent inhibitor
Epigenetic inhibitors
Lysine methyltransferase
SMYD3

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