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Bioorg Med Chem. 2016 Sep 15;24(18):4008-4015. doi: 10.1016/j.bmc.2016.06.040. Epub 2016 Jun 22.

Kinetic and structural insights into the binding of histone deacetylase 1 and 2 (HDAC1, 2) inhibitors.

Author information

1
Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, 75 Ames Street, Cambridge, MA, USA. Electronic address: fwagner@broadinstitute.org.
2
Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, 75 Ames Street, Cambridge, MA, USA.
3
Proteros Biostructures GmbH, Bunsenstr. 7a, 82152 Martinsried, Germany.
4
SL Fisher Consulting, LLC, 18 Harrington Road, Framingham, MA, USA.
5
Chemical Neurobiology Laboratory, Center for Human Genetic Research, Massachusetts General Hospital, Department of Neurology and Psychiatry, Harvard Medical School, Boston, MA, USA.
6
X-ray Diffraction Facility, MIT Department of Chemistry, 77 Massachussetts Avenue, 2-325, Cambridge, MA, USA.
7
Rodin Therapeutics Inc., 400 Technology Square, 10th Floor, Cambridge, MA, USA.
8
Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, 75 Ames Street, Cambridge, MA, USA. Electronic address: EHolson@atlasventure.com.

Abstract

The structure-activity and structure-kinetic relationships of a series of novel and selective ortho-aminoanilide inhibitors of histone deacetylases (HDACs) 1 and 2 are described. Different kinetic and thermodynamic selectivity profiles were obtained by varying the moiety occupying an 11Å channel leading to the Zn(2+) catalytic pocket of HDACs 1 and 2, two paralogs with a high degree of structural similarity. The design of these novel inhibitors was informed by two ligand-bound crystal structures of truncated hHDAC2. BRD4884 and BRD7232 possess kinetic selectivity for HDAC1 versus HDAC2. We demonstrate that the binding kinetics of HDAC inhibitors can be tuned for individual isoforms in order to modulate target residence time while retaining functional activity and increased histone H4K12 and H3K9 acetylation in primary mouse neuronal cell culture assays. These chromatin modifiers, with tuned binding kinetic profiles, can be used to define the relation between target engagement requirements and the pharmacodynamic response of HDACs in different disease applications.

KEYWORDS:

Acetylation; HDAC inhibitors; Isoform selectivity; Kinetic selectivity; Target engagement

PMID:
27377864
DOI:
10.1016/j.bmc.2016.06.040
[Indexed for MEDLINE]

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