Targeting Class IIa HDACs: Insights from Phenotypes and Inhibitors.
Fiche publication
Date publication
juin 2021
Journal
Current medicinal chemistry
Auteurs
Membres identifiés du Cancéropôle Est :
Dr BOURGUET Erika
Tous les auteurs :
Liu L, Dong L, Bourguet E, Fairlie DP
Lien Pubmed
Résumé
This review summarizes key literature defining the phenotypes of individual class IIa HDAC proteins and compounds that selectively target their enzymatic catalytic domain (CD). The focus is on the effects of class IIa HDACs in physiological and pathological conditions, both in vitro and in vivo, and their mode of action in regulating genes, upstream proteins and signaling pathways. Phenotype studies further demonstrate either beneficial or detrimental effects of silencing selected class IIa HDACs or their enzymatic properties. We also summarize the knowledge gained from structure-activity relationships of CD inhibitors as well as molecular mechanisms underpinning isozyme selectivity where crystal structures or modelling studies were available. Given that the numbers of genes affected by silencing class IIa HDACs are much smaller than class I, the role of gene regulation of class IIa HDACs could be much more selective. Since class IIa HDACs have restricted tissue distributions and multiple functions independent of their CD, targeting the CD of class IIa HDACs could lead to more selective therapeutic agents with significantly fewer side-effects than for other HDAC ligands.
Mots clés
HDAC isoforms, catalytic domain inhibitor , class IIa HDAC, drug discovery, epigenetic regulation, histone deacetylase, inhibitor, phenotype
Référence
Curr Med Chem. 2021 Jun 29;: