On the histone lysine methyltransferase activity of fungal metabolite chaetocin.

Journal article

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.

Authors: Cherblanc, F; Chapman, K; Reid, J; Borg, A; Sundriyal, S

• Publication status: Published
• Journal: Journal of medicinal chemistry
• Volume: 56
• Issue: 21
• Pages: 8616-8625
• Publication date: 2013-11-01
• DOI: 10.1021/jm401063r
• EISSN: 1520-4804
• ISSN: 0022-2623
• Language: English
• Keywords: Models, Molecular; Histone-Lysine N-Methyltransferase; Humans; Recombinant Proteins; Enzyme Inhibitors; Dose-Response Relationship, Drug; Chaetomium; Molecular Conformation; Piperazines; Structure-Activity Relationship