1. Design, Synthesis, and Biological Activity of Substrate Competitive SMYD2 Inhibitors.
- Author
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Cowen SD, Russell D, Dakin LA, Chen H, Larsen NA, Godin R, Throner S, Zheng X, Molina A, Wu J, Cheung T, Howard T, Garcia-Arenas R, Keen N, Pendleton CS, Pietenpol JA, and Ferguson AD
- Subjects
- Cell Line, Tumor, Cell Proliferation drug effects, Dose-Response Relationship, Drug, Enzyme Inhibitors chemical synthesis, Enzyme Inhibitors chemistry, HCT116 Cells, Histone-Lysine N-Methyltransferase metabolism, Humans, Molecular Structure, Structure-Activity Relationship, Drug Design, Enzyme Inhibitors pharmacology, Histone-Lysine N-Methyltransferase antagonists & 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.
- Published
- 2016
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