Kinetic Tuning of HDAC Inhibitors Affords Potent Inducers of Progranulin Expression.

ABSTRACT: Histone deacetylases (HDACs) are enzymes involved in the epigenetic control of gene expression. A handful of HDAC inhibitors have been approved for the treatment of cancer, and HDAC inhibition has also been proposed as a novel therapeutic strategy for neurodegenerative disorders. These disorders include progranulin (PGRN)-deficient forms of frontotemporal dementia caused by mutations in the GRN gene that lead to haploinsufficiency. Hydroxamic-acid-based inhibitors of HDACs 1-3, reported to have fast-on/fast-off binding kinetics, induce increased expression of PGRN in human neuronal models, while the benzamide class of slow-binding HDAC inhibitors does not produce this effect. These observations indicate that the kinetics of HDAC inhibitor binding can be tuned for optimal induction o

SUBMITTER: Moreno-Yruela C 

PROVIDER: S-EPMC6982123 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature