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ACS Med Chem Lett. 2014 Jan 2;5(4):340-5. doi: 10.1021/ml4004233. eCollection 2014 Apr 10.

Delayed and Prolonged Histone Hyperacetylation with a Selective HDAC1/HDAC2 Inhibitor.

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1
Merck Research Laboratories , 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.

Abstract

The identification and in vitro and in vivo characterization of a potent SHI-1:2 are described. Kinetic analysis indicated that biaryl inhibitors exhibit slow binding kinetics in isolated HDAC1 and HDAC2 preparations. Delayed histone hyperacetylation and gene expression changes were also observed in cell culture, and histone acetylation was observed in vivo beyond disappearance of drug from plasma. In vivo studies further demonstrated that continuous target inhibition was well tolerated and efficacious in tumor-bearing mice, leading to tumor growth inhibition with either once-daily or intermittent administration.

KEYWORDS:

Histone acetylation; histone deacetylase inhibitor; isoform selectivity; kinetics

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