On the Histone Lysine Methyltransferase Activity of Fungal Metabolite Chaetocin

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 an...

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Published in:Journal of medicinal chemistry 2013-11, Vol.56 (21), p.8616-8625
Main Authors: Cherblanc, Fanny L, Chapman, Kathryn L, Reid, Jim, Borg, Aaron J, Sundriyal, Sandeep, Alcazar-Fuoli, Laura, Bignell, Elaine, Demetriades, Marina, Schofield, Christopher J, DiMaggio, Peter A, Brown, Robert, Fuchter, Matthew J
Format: Article
Language:English
Subjects:
Chaetomium - chemistry
Chaetomium - metabolism
Dose-Response Relationship, Drug
Enzyme Inhibitors - chemistry
Enzyme Inhibitors - metabolism
Enzyme Inhibitors - pharmacology
Histone-Lysine N-Methyltransferase - antagonists & inhibitors
Histone-Lysine N-Methyltransferase - metabolism
Humans
Models, Molecular
Molecular Conformation
Piperazines - chemistry
Piperazines - metabolism
Piperazines - pharmacology
Recombinant Proteins - metabolism
Structure-Activity Relationship
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Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm401063r