| 1. |
- Parenti, Marco Daniele, et al.
(författare)
-
Discovery of the 4-aminopiperidine-based compound EM127 for the site-specific covalent inhibition of SMYD3
- 2022
-
Ingår i: European Journal of Medicinal Chemistry. - : Elsevier. - 0223-5234 .- 1768-3254. ; 243
-
Tidskriftsartikel (refereegranskat)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-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.
|
|
| 2. |
- Talibov, Vladimir O, 1991-, et al.
(författare)
-
Discovery of an allosteric ligand binding site in SMYD3 lysine methyltransferase
- 2021
-
Ingår i: ChemBioChem. - : Wiley. - 1439-4227 .- 1439-7633. ; 22:9, s. 1597-1608
-
Tidskriftsartikel (refereegranskat)abstract
- SMYD3 is a multifunctional epigenetic enzyme with lysine methyl transferase activity and various interaction partners. It is implicated in the pathophysiology of cancers but with an unclear mechanism. To discover tool compounds for clarifying its biochemistry and potential as a therapeutic target, a set of drug-like compounds was screened using a biosensor-based competition assay. Diperodon was identified as an allosteric ligand. The ( R )-and ( S )-enantiomers of the racemic drug were isolated and their affinities determined ( K D > = 42 and 84 ÎŒM). Co-crystallization revealed that both enantiomers bind to a previously unidentified allosteric site in the C-terminal protein binding domain, consistent with its weak inhibitory effect. No competition between diperodon and HSP90 (a known SMYD3 interaction partner) was observed although HSP90-SMYD3 binding was confirmed ( K D = 13 ÎŒM). The allosteric site appears to be druggable and suitable for exploration of non-catalytic SMYD3 functions and therapeutics with new mechanisms of action.
|
|
