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

Parenti, Marco Daniele ; Naldi, Marina ; Manoni, Elisabetta ; Fabini, Edoardo ; Cederfelt, Daniela ; Talibov, Vladimir O. LU orcid ; Gressani, Valeria ; Guven, Ummu ; Grossi, Valentina and Fasano, Candida , et al. (2022) In European Journal of Medicinal Chemistry 243.
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,... (More)

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 μM) 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.

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publishing date
type
Contribution to journal
publication status
published
subject
keywords
Cancer target therapy, Covalent inhibitor, Epigenetic inhibitors, Lysine methyltransferase, SMYD3
in
European Journal of Medicinal Chemistry
volume
243
article number
114683
publisher
Elsevier Masson SAS
external identifiers
  • pmid:36116234
  • scopus:85138099182
ISSN
0223-5234
DOI
10.1016/j.ejmech.2022.114683
language
English
LU publication?
yes
id
69e4fd04-a282-449a-bcd5-b9e41ddefc1a
date added to LUP
2022-12-01 15:05:23
date last changed
2024-04-18 04:45:41
@article{69e4fd04-a282-449a-bcd5-b9e41ddefc1a,
  abstract     = {{<p>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 μM) 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.</p>}},
  author       = {{Parenti, Marco Daniele and Naldi, Marina and Manoni, Elisabetta and Fabini, Edoardo and Cederfelt, Daniela and Talibov, Vladimir O. and Gressani, Valeria and Guven, Ummu and Grossi, Valentina and Fasano, Candida and Sanese, Paola and De Marco, Katia and Shtil, Alexander A. and Kurkin, Alexander V. and Altieri, Andrea and Danielson, U. Helena and Caretti, Giuseppina and Simone, Cristiano and Varchi, Greta and Bartolini, Manuela and Del Rio, Alberto}},
  issn         = {{0223-5234}},
  keywords     = {{Cancer target therapy; Covalent inhibitor; Epigenetic inhibitors; Lysine methyltransferase; SMYD3}},
  language     = {{eng}},
  month        = {{12}},
  publisher    = {{Elsevier Masson SAS}},
  series       = {{European Journal of Medicinal Chemistry}},
  title        = {{Discovery of the 4-aminopiperidine-based compound EM127 for the site-specific covalent inhibition of SMYD3}},
  url          = {{http://dx.doi.org/10.1016/j.ejmech.2022.114683}},
  doi          = {{10.1016/j.ejmech.2022.114683}},
  volume       = {{243}},
  year         = {{2022}},
}