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Development of a histone deacetylase 6 inhibitor and its biological effects.


ABSTRACT: Development of isoform-selective histone deacetylase (HDAC) inhibitors is important in elucidating the function of individual HDAC enzymes and their potential as therapeutic agents. Among the eleven zinc-dependent HDACs in humans, HDAC6 is structurally and functionally unique. Here, we show that a hydroxamic acid-based small-molecule N-hydroxy-4-(2-[(2-hydroxyethyl)(phenyl)amino]-2-oxoethyl)benzamide (HPOB) selectively inhibits HDAC6 catalytic activity in vivo and in vitro. HPOB causes growth inhibition of normal and transformed cells but does not induce cell death. HPOB enhances the effectiveness of DNA-damaging anticancer drugs in transformed cells but not normal cells. HPOB does not block the ubiquitin-binding activity of HDAC6. The HDAC6-selective inhibitor HPOB has therapeutic potential in combination therapy to enhance the potency of anticancer drugs.

SUBMITTER: Lee JH 

PROVIDER: S-EPMC3785767 | biostudies-literature | 2013 Sep

REPOSITORIES: biostudies-literature

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Development of a histone deacetylase 6 inhibitor and its biological effects.

Lee Ju-Hee JH   Mahendran Adaickapillai A   Yao Yuanshan Y   Ngo Lang L   Venta-Perez Gisela G   Choy Megan L ML   Kim Nathaniel N   Ham Won-Seok WS   Breslow Ronald R   Marks Paul A PA  

Proceedings of the National Academy of Sciences of the United States of America 20130910 39


Development of isoform-selective histone deacetylase (HDAC) inhibitors is important in elucidating the function of individual HDAC enzymes and their potential as therapeutic agents. Among the eleven zinc-dependent HDACs in humans, HDAC6 is structurally and functionally unique. Here, we show that a hydroxamic acid-based small-molecule N-hydroxy-4-(2-[(2-hydroxyethyl)(phenyl)amino]-2-oxoethyl)benzamide (HPOB) selectively inhibits HDAC6 catalytic activity in vivo and in vitro. HPOB causes growth in  ...[more]

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