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Novel histone deacetylase 8 ligands without a zinc chelating group: exploring an 'upside-down' binding pose.

ABSTRACT: A novel series of HDAC8 inhibitors without a zinc-chelating hydroxamic acid moiety is reported. Photoaffinity labeling and molecular modeling studies suggest that these ligands are likely to bind in an 'upside-down' fashion in a secondary binding site proximal to the main catalytic site. The most potent ligand in the series exhibits an IC(50) of 28 ?M for HDAC8 and is found to inhibit the deacetylation of H4 but not ?-tubulin in SH-SY5Y cell line.

SUBMITTER: Vaidya AS

PROVIDER: S-EPMC3472134 | biostudies-literature | 2012 Nov

REPOSITORIES: biostudies-literature

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Novel histone deacetylase 8 ligands without a zinc chelating group: exploring an 'upside-down' binding pose.

Vaidya Aditya Sudheer AS Neelarapu Raghupathi R Madriaga Antonett A Bai He H Mendonca Emma E Abdelkarim Hazem H van Breemen Richard B RB Blond Sylvie Y SY Petukhov Pavel A PA

Bioorganic & medicinal chemistry letters 20120907 21

A novel series of HDAC8 inhibitors without a zinc-chelating hydroxamic acid moiety is reported. Photoaffinity labeling and molecular modeling studies suggest that these ligands are likely to bind in an 'upside-down' fashion in a secondary binding site proximal to the main catalytic site. The most potent ligand in the series exhibits an IC(50) of 28 μM for HDAC8 and is found to inhibit the deacetylation of H4 but not α-tubulin in SH-SY5Y cell line. ...[more]

PMID: 23010266

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