Smyd3 is a SET-domain containing lysine methyltransferase that methylates both histone and non-histone proteins. Smyd3 methylation at MEKK2 lysine 260 (K260) has been reported to disrupt the interaction of MEKK2 with the inhibitory PP2A phosphatase, resulting in elevated phospho-ERK1/2 and phospho-ERK5. Additionally, Smyd3 is overexpressed in several tumor cell lines including colorectal carcinoma, breast cancer cells, and hepatocellular carcinoma. Lowering Smyd3 expression through treatment with small interfering RNA duplexes results in significantly suppressed growth in several cancer cell lines, suggesting that Smyd3 plays an important role in tumor proliferation. A three-pronged screening approach which included an HTS campaign, ELT screen, and a fragment screen, followed by lead optimization delivered multiple chemical series for key target validation studies. Several compounds exhibited excellent potency in the biochemical and cellular assays and demonstrated target engagement, however, failed to show anti-proliferative activity or changes in downstream pERK signaling.

SMYD3 target (in)validation from a medicinal chemistry perspective

2019 Spring National Meeting

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