Isoform-selective HDAC1/6/8 inhibitors with an imidazo-ketopiperazine cap containing stereochemical diversity.
Fiche publication
Date publication
juin 2018
Journal
Philosophical transactions of the Royal Society of London. Series B, Biological sciences
Auteurs
Membres identifiés du Cancéropôle Est :
Dr ROMIER Christophe
Tous les auteurs :
Lecointre B, Narozny R, Borrello MT, Senger J, Chakrabarti A, Jung M, Marek M, Romier C, Melesina J, Sippl W, Bischoff L, Ganesan A
Lien Pubmed
Résumé
A series of hydroxamic acids linked by different lengths to a chiral imidazo-ketopiperazine scaffold were synthesized. The compounds with linker lengths of 6 and 7 carbon atoms were the most potent in histone deacetylase (HDAC) inhibition, and were specific submicromolar inhibitors of the HDAC1, HDAC6 and HDAC8 isoforms. A docking model for the binding mode predicts binding of the hydroxamic acid to the active site zinc cation and additional interactions between the imidazo-ketopiperazine and the enzyme rim. The compounds were micromolar inhibitors of the MV4-11, THP-1 and U937 cancer cell lines. Increased levels of histone H3 and tubulin acetylation support a cellular mechanism of action through HDAC inhibition.This article is part of a discussion meeting issue 'Frontiers in epigenetic chemical biology'.
Mots clés
enzyme inhibitors, epigenetics, histone deacetylases, peptidomimetics, zinc metalloenzymes
Référence
Philos. Trans. R. Soc. Lond., B, Biol. Sci.. 2018 Jun 5;373(1748):