Title:Targeting Class IIa HDACs: Insights from Phenotypes and Inhibitors
Volume: 28
Issue: 42
关键词:
药物发现，表观遗传调控，表型，组蛋白去乙酰化酶，HDAC异构体，IIa类HDAC，抑制剂，催化域抑制剂。
摘要: 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 on 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 are available. Given that the number of genes affected by silencing class IIa
HDACs is 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 other HDAC ligands.
