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On the histone lysine methyltransferase activity of fungal metabolite chaetocin.

Abstract：

: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.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Cherblanc FL,Chapman KL,Reid J,Borg AJ,Sundriyal S,Alcazar-Fuoli L,Bignell E,Demetriades M,Schofield CJ,DiMaggio PA Jr,Brown R,Fuchter MJ

doi

10.1021/jm401063r

subject

Has Abstract

pub_date

2013-11-14 00:00:00

pages

8616-25

issue

21

eissn

0022-2623

issn

1520-4804

journal_volume

56

pub_type

杂志文章

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