Discovery of Irreversible Inhibitors Targeting Histone Methyltransferase, SMYD3

Abstract

SMYD3 is a histone methyltransferase that regulates gene transcription, and its overexpression is associated with multiple human cancers. A novel class of tetrahydroacridine compounds which inhibit SMYD3 through a covalent mechanism of action is identified. Optimization of these irreversible inhibitors resulted in the discovery of 4chloroquinolines, a new class of covalent warheads. Tool compound 29 exhibits high potency by inhibiting SMYD3′s enzymatic activity and showing antiproliferative activity against HepG2 in 3D cell culture. Our findings suggest that covalent inhibition of SMYD3 may have an impact on SMYD3 biology by affecting expression levels, and this warrants further exploration.

SMYD3: An Oncogenic Driver Targeting Epigenetic Regulation and Signaling Pathways

“…These molecules represent potent SMYD3 inhibitors, are chemically less reactive than classical inhibitors, and were shown to decrease cell growth in HepG2 cells. In addition, they were able to block MAP3K2 methylation in HepG2 cells [97].…”

Human Emotion Recognition: Review of Sensors and Methods

“…The heart rate represents the net effect of the parasympathetic nerves, which slow heartrate, and the sympathetic nerves, which accelerate it. These changes are influenced by emotions, stress, and physical exercise [98,99]. Moreover, HRV depends on age and gender, and additional factors include physical and mental stress, smoking, alcohol, coffee, overweight, and blood pressure, as well as glucose level, infectious agents, and depression.…”

SMYD3: a regulator of epigenetic and signaling pathways in cancer

“…This is a novel class of inhibitors that inhibit SMYD3 irreversibly via covalent modifications, specifically a nucleophilic aromatic substitution reaction [ 90 ]. In vitro, some of these compounds had an antiproliferative effect on the HepG2 cell line, a hepatocellular carcinoma cell line [ 90 ]. Further investigation into the in vivo effects of these compounds is necessary, but early data are promising [ 90 ].…”

“…In vitro, some of these compounds had an antiproliferative effect on the HepG2 cell line, a hepatocellular carcinoma cell line [ 90 ]. Further investigation into the in vivo effects of these compounds is necessary, but early data are promising [ 90 ].…”