Journal
JOURNAL OF BIOMOLECULAR SCREENING
Volume 17, Issue 10, Pages 1279-1292Publisher
SAGE PUBLICATIONS INC
DOI: 10.1177/1087057112453765
Keywords
epigenetics; histone methyltransferase; EZH2; HTS
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Histone methyltransferases (HMT) catalyze the methylation of histone tail lysines, resulting in changes in gene transcription. Misregulation of these enzymes has been associated with various forms of cancer, making this target class a potential new area for the development of novel chemotherapeutics. EZH2 is the catalytic component of the polycomb group repressive complex (PRC2), which selectively methylates histone H3 lysine 27 (H3K27). EZH2 is overexpressed in prostate, breast, bladder, brain, and other tumor types and is recognized as a molecular marker for cancer progression and aggressiveness. Several new reagents and assays were developed to aid in the identification of EZH2 inhibitors, and these were used to execute two high-throughput screening campaigns. Activity assays using either an H3K27 peptide or nucleosomes as substrates for methylation are described. The strategy to screen EZH2 with either a surrogate peptide or a natural substrate led to the identification of the same tractable series. Compounds from this series are reversible, are [H-3]-S-adenosyl-L-methionine competitive, and display biochemical inhibition of H3K27 methylation.
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