Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 56, Issue 21, Pages 8616-8625Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jm401063r
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Funding
- Cancer Research U.K. [C21484A6944, C536/A13086]
- European Union [PIIF-GA-2011-299857]
- Cancer Research UK [6944, 13086] Funding Source: researchfish
- Ovarian Cancer Action [OCA3] Funding Source: researchfish
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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.
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