Design, Synthesis, and Biological Activity of Substrate Competitive SMYD2 Inhibitors

Abstract

Protein lysine methyltransferases (KMTs) have emerged as important regulators of epigenetic signaling. These enzymes catalyze the transfer of donor methyl groups from the cofactor S-adenosylmethionine to specific acceptor lysine residues on histones, leading to changes in chromatin structure and transcriptional regulation. These enzymes also methylate an array of nonhistone proteins, suggesting additional mechanisms by which they influence cellular physiology. SMYD2 is reported to be an oncogenic methyltransferase that represses the functional activity of the tumor suppressor proteins p53 and RB. HTS screening led to identification of five distinct substrate-competitive chemical series. Determination of liganded crystal structures of SMYD2 contributed significantly to "hit-to-lead" design efforts, culminating in the creation of potent and selective inhibitors that were used to understand the functional consequences of SMYD2 inhibition. Taken together, these results have broad implications for inhibitor design against KMTs and clearly demonstrate the potential for developing novel therapies against these enzymes.

Collaboration of MYC and RUNX2 in lymphoma simulates T‐cell receptor signaling and attenuates p53 pathway activity

“…The most highly upregulated was Smyd2, a gene encoding a lysine methyltransferase that has been associated with poor prognosis in a wide range of leukemias and solid tumors 37,57-60 and has been targeted for drug development. 40,41,45 Our results confirm recent findings that the reported SMYD2 inhibitors behave discordantly because of off-target effects, and the resistance of RUNX2/MYC cell lines to specific inhibitors recapitulates a wider CRISPR-Cas study of cancer cell lines. 44 However, RUNX2/MYC lines show consistent deletion of p53, whereas primary tumors and transplanted lymphomas often retain the wildtype allele, 18 arguing that in vivo and in vitro growth selection are markedly different processes.…”

The Promise for Histone Methyltransferase Inhibitors for Epigenetic Therapy in Clinical Oncology: A Narrative Review

“…A recent report found abundant expression of SMYD2 to be an independent biomarker for poor prognosis of patients with hepatocellular carcinoma, which might imply that SMYD2 overexpression is associated with a more aggressive phenotype [ 169 ]. Potent and selective SMYD2 inhibitors have been developed to interrogate this potentially important anticancer approach [ 170 – 172 ].…”

A functional proteomics platform to reveal the sequence determinants of lysine methyltransferase substrate selectivity

“…This is the same pocket occupied by AZ506, a recently found small-molecule inhibitor of SMYD2 (fig. S4E) ( 26 ). Overall, the MD simulations revealed unique interactions for both PER2 and WKLKSKR, which likely contribute to the faster methylation rates observed for these peptides.…”