On the Histone Lysine Methyltransferase Activity of Fungal Metabolite Chaetocin

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• 作者：Fanny L. Cherblanc ; Kathryn L. Chapman ; Jim Reid ; Aaron J. Borg ; Sandeep Sundriyal ; Laura Alcazar-Fuoli ; Elaine Bignell ; Marina Demetriades ; Christopher J. Schofield ; Peter A. DiMaggio ; Jr ; Robert Brown ; Matthew J. Fuchter
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：November 14, 2013
• 年：2013
• 卷：56
• 期：21
• 页码：8616-8625
• 全文大小：485K
• 年卷期：v.56,no.21(November 14, 2013)
• ISSN：1520-4804

文摘

Histone lysine methyltransferases (HKMTs) are an important class of targets for epigenetic therapy. 1 (chaetocin), an epidithiodiketopiperazine (ETP) natural product, has been reported to be a specific inhibitor of the SU(VAR)3-9 class of HKMTs. We have studied the inhibition of the HKMT G9a by 1 and functionally related analogues. Our results reveal that only the structurally unique ETP core is required for inhibition, and such inhibition is time-dependent and irreversible (in the absence of DTT), ultimately resulting in protein denaturation. Mass spectrometric data provide a molecular basis for this effect, demonstrating covalent adduct formation between 1 and the protein. This provides a potential rationale for the selectivity observed in the inhibition of a variety of HKMTs by 1 in vitro and has implications for the activity of ETPs against these important epigenetic targets.