SMYD3 is a methyltransferase (MTase) catalyzing the methylation of specific lysine residues. Notably, it induces cell proliferation and regulates gene expression, including histones H3 (Histone H3 Lysine 4, H3K4) and H4 (Histone H4 Lysine 5, VEGFR1 receptor, AKT1, HER2, and MAP3K2 protein. Importantly, SMYD3 plays a role in transcriptional regulation as a member of an RNA polymerase complex. Besides, SMYD3 trimethylates a lysine residue on MAP3K2, which causes crosstalk into the MAP kinase signaling pathway in Ras-driven cancers.

SMYD3 plays an important role in the progression of cancers in humans. It is highly overexpressed in several cancers such as liver, breast, and colorectal carcinomas. Moreover, SMYD3 overexpression has also been correlated with poor prognosis in non-small cell lung cancer, and hepatocellular carcinoma and its inhibition has been shown to reduce tumor growth in animal models. Here, we will introduce a SMYD3 Covalent Inhibitor for cancer.

EM127 is a potent, selectivity, high affinity, and site-specificity SMYD3 covalent inhibitor.

EM127 (5 μM; 24, 48, 72 h) shows good anti-proliferative activity in MDA-MB-231and HCT116 cells. Besides, this compound (5 μM; 24, 48, 72 h) attenuates the expression of SMYD3 target genes while not affecting expression when SMYD3 at low levels in MDA-MB-231 cells. specifically, EM127 (0.5, 3.5, 5 μM; 48 h) significantly reduces the expression of CDK2 and C-MET, the known SMYD3-regulated genes. It decreases the abundance of mRNAs of the extracellular matrix component fibronectin 1 (FN1) and N-cadherin (N-CAD) in MDA-MB-231 cells. In addition, EM127 (1, 3.5, 5 μM; 48, 72 h) decreases ERK1/2 phosphorylation in a dose- and time-dependent manner in HCT116 and MDA-MB-231cells.

All in all, EM127 is a potent and selectivity SMYD3 covalent inhibitor with a KD value of 13 μM. Additionally, EM127 effectively impairs methyltransferase activity and has the potential for research in SMYD3-positive tumors.


[1] Parenti MD, et al. Eur J Med Chem. 2022 Sep 8;243:114683.