Highlights

• ZYZ-803 is a newly developed small molecule that directly inhibits SMYD3’s methyltransferase activity on H3K4.
• The study confirms that blocking SMYD3 with ZYZ-803 suppresses tumor progression in hepatocellular carcinoma models.
• This is one of the first demonstrations of a small molecule effectively disrupting SMYD3-H3K4 methylation as a therapeutic strategy for HCC.

Summary

The research article presents the discovery and evaluation of ZYZ384,

a novel small-molecule inhibitor targeting SMYD3, a histone lysine methyltransferase frequently overexpressed in cancers including hepatocellular carcinoma (HCC). Through structure-based virtual screening and rational modification, ZYZ384 was identified as a potent and selective binder of SMYD3. Biochemical and cellular assays confirmed its ability to inhibit SMYD3 methyltransferase activity, leading to reduced H3K4 trimethylation at the promoter of Rac1—an event implicated in oncogenic signaling.

In vitro, ZYZ384 exhibited selective anti-proliferative effects against multiple cancer cell lines, with pronounced activity in HepG2 cells, while showing minimal toxicity in normal hepatocytes. In vivo, ZYZ384 administration significantly suppressed tumor growth in a HCC xenograft model. Integrated RNA-seq and ChIP-seq analyses revealed that ZYZ384 impairs tumor progression by inducing cell cycle arrest via transcriptional modulation of the AKT pathway.

These results establish ZYZ384 as a promising epigenetic-based therapeutic candidate for HCC, acting through selective SMYD3 inhibition and downstream disruption of H3K4me3-dependent oncogenic signaling.

Q. Ding et al., “A novel small molecule ZYZ384 targeting SMYD3 for hepatocellular carcinoma via reducing H3K4 trimethylation of the Rac1 promoter,” MedComm, vol. 5, no. 10, p. e711, Oct. 2024, doi: 10.1002/mco2.711.