4.7 Article

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

期刊

出版社

ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2022.114683

关键词

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

资金

  1. Italian Association for Cancer Research (AIRC) [IG 19172, IG 23794, IG 21353]
  2. Emilia Romagna region POR FSE 2014/2020 project ONCO- PENTA
  3. RFBR [20-53-7808]
  4. Bilateral CNR/RFBR grant
  5. Italian Ministry of Health [SG -2019-12371540]
  6. Italian Ministry of Education, University and Research (MIUR) PRIN-Research Projects of National Relevance(PRIN 2017) [2017WNKSLRLS4]
  7. Cariplo [2017-0604]

向作者/读者索取更多资源

Recent findings suggest that inhibiting SMYD3 methyltransferase could be a therapeutic strategy for certain deadly cancer types. This study designed active site-selective covalent SMYD3 inhibitors and demonstrated their ability to attenuate tumor biology at the cellular and genetic levels, inhibiting important genes and cell proliferation.
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.

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