Dissecting structure-activity-relationships of crebinostat: Brain penetrant HDAC inhibitors for neuroepigenetic regulation

Balaram Ghosh; Wen-Ning Zhao; Surya A Reis; Debasis Patnaik; Daniel M Fass; Li-Huei Tsai; Ralph Mazitschek; Stephen J Haggarty

doi:10.1016/j.bmcl.2016.01.022

Dissecting structure-activity-relationships of crebinostat: Brain penetrant HDAC inhibitors for neuroepigenetic regulation

Bioorg Med Chem Lett. 2016 Feb 15;26(4):1265-1271. doi: 10.1016/j.bmcl.2016.01.022. Epub 2016 Jan 11.

Authors

Balaram Ghosh^#^{1

2}, Wen-Ning Zhao^#^{1

2}, Surya A Reis^{1

2}, Debasis Patnaik^{1

2}, Daniel M Fass^{1

2}, Li-Huei Tsai³, Ralph Mazitschek⁴, Stephen J Haggarty^{1

2}

Affiliations

¹ Chemical Neurobiology Laboratory, Center for Human Genetic Research, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, USA.
² Departments of Psychiatry & Neurology, Massachusetts General Hospital & Harvard Medical School, Boston, MA 02114, USA.
³ Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
⁴ Center for Systems Biology, Massachusetts General Hospital, 185 Cambridge Street, Boston, Massachusetts 02114, USA.

^# Contributed equally.

Abstract

Targeting chromatin-mediated epigenetic regulation has emerged as a potential avenue for developing novel therapeutics for a wide range of central nervous system disorders, including cognitive disorders and depression. Histone deacetylase (HDAC) inhibitors have been pursued as cognitive enhancers that impact the regulation of gene expression and other mechanisms integral to neuroplasticity. Through systematic modification of the structure of crebinostat, a previously discovered cognitive enhancer that affects genes critical to memory and enhances synaptogenesis, combined with biochemical and neuronal cell-based screening, we identified a novel hydroxamate-based HDAC inhibitor, here named neurinostat, with increased potency compared to crebinostat in inducing neuronal histone acetylation. In addition, neurinostat was found to have a pharmacokinetic profile in mouse brain modestly improved over that of crebinostat. This discovery of neurinostat and demonstration of its effects on neuronal HDACs adds to the available pharmacological toolkit for dissecting the molecular and cellular mechanisms of neuroepigenetic regulation in health and disease.

Keywords: Acetylation; CREB; Chromatin; Cognitive enhancer; Epigenetic; Histone deacetylases; Neuroepigenetic; Nootropic.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Acetylation
Animals
Biphenyl Compounds / chemical synthesis
Biphenyl Compounds / chemistry*
Biphenyl Compounds / pharmacokinetics
Brain / metabolism*
Cells, Cultured
Half-Life
Histone Deacetylase Inhibitors / chemical synthesis
Histone Deacetylase Inhibitors / chemistry*
Histone Deacetylase Inhibitors / pharmacokinetics
Histone Deacetylases / chemistry
Histone Deacetylases / metabolism*
Histones / metabolism
Hydrazines / chemical synthesis
Hydrazines / chemistry*
Hydrazines / pharmacokinetics
Inhibitory Concentration 50
Mice
Neurons / cytology
Neurons / metabolism
Protein Binding
Structure-Activity Relationship

Substances

(7-(2-((1,1'-biphenyl)-4-ylmethylene)hydrazinyl)-N-hydroxy-7-oxoheptanamide)
Biphenyl Compounds
Histone Deacetylase Inhibitors
Histones
Hydrazines
Histone Deacetylases

Abstract

Publication types

MeSH terms

Substances

Grants and funding