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ACS Chem Neurosci. 2019 Aug 21;10(8):3769-3777. doi: 10.1021/acschemneuro.9b00281. Epub 2019 Aug 5.

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

Author information

1
Center for Biopharmaceuticals & Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences , University of Copenhagen , DK-2100 Copenhagen , Denmark.
2
Chemical Neurobiology Laboratory, Center for Genomic Medicine, Departments of Neurology & Psychiatry , Massachusetts General Hospital and Harvard Medical School , 185 Cambridge Street , Boston , Massachusetts 02114 , United States.
3
Departments of Molecular Genetics, Neuroscience, Neurology and Neurotherapeutics, Center for Translational Neurodegeneration Research , University of Texas Southwestern Medical Center at Dallas , Dallas , Texas 75390-9046 , United States.

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 of human PGRN expression in neurons. Here, we further expand on these findings using human cortical-like, glutamatergic neurons. We provide evidence that two prototypical, potent hydroxamic acid HDAC inhibitors that induce PGRN (panobinostat and trichostatin A) exhibit an initial fast-binding step followed by a second, slower step, referred to as mechanism B of slow binding, rather than simpler fast-on/fast-off binding kinetics. In addition, we show that trapoxin A, a macrocyclic, epoxyketone-containing class I HDAC inhibitor, exhibits slow binding with high, picomolar potency and also induces PGRN expression in human neurons. Finally, we demonstrate induction of PGRN expression by fast-on/fast-off, highly potent, macrocyclic HDAC inhibitors with ethyl ketone or ethyl ester Zn2+ binding groups. Taken together, these data expand our understanding of HDAC1-3 inhibitor binding kinetics, and further delineate the specific combinations of structural and kinetic features of HDAC inhibitors that are optimal for upregulating PGRN expression in human neurons and thus may have translational relevance in neurodegenerative disease.

KEYWORDS:

Epigenetic; histone deacetylase; kinetic profiling; panobinostat; progranulin; slow-binding inhibitor

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