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Adding a lysine mimic in the design of potent inhibitors of histone lysine methyltransferases.

Chang Y, Ganesh T, Horton JR, Spannhoff A, Liu J, Sun A, Zhang X, Bedford MT, Shinkai Y, Snyder JP, Cheng X
J Mol Biol 400 1-7 (2010)
Related entries: 3mo0, 3mo2

Cited: 64 times
EuropePMC logo PMID: 20434463

Abstract

Dynamic histone lysine methylation involves the activities of modifying enzymes (writers), enzymes removing modifications (erasers), and readers of the histone code. One common feature of these activities is the recognition of lysines in methylated and unmethylated states, whether they are substrates, reaction products, or binding partners. We applied the concept of adding a lysine mimic to an established inhibitor (BIX-01294) of histone H3 lysine 9 methyltransferases G9a and G9a-like protein by including a 5-aminopentyloxy moiety, which is inserted into the target lysine-binding channel and becomes methylated by G9a-like protein, albeit slowly. The compound enhances its potency in vitro and reduces cell toxicity in vivo. We suggest that adding a lysine or methyl-lysine mimic should be considered in the design of small-molecule inhibitors for other methyl-lysine writers, erasers, and readers.

Reviews - 3mo5 mentioned but not cited (2)

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  2. Modulation of epigenetic targets for anticancer therapy: clinicopathological relevance, structural data and drug discovery perspectives. Andreoli F, Barbosa AJ, Parenti MD, Del Rio A. Curr Pharm Des 19 578-613 (2013)

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