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Methot JL, Hoffman DM, Witter DJ, et al. Delayed and Prolonged Histone Hyperacetylation with a Selective HDAC1/HDAC2 Inhibitor. ACS Med Chem Lett. 2014;5(4):340-5doi: 10.1021/ml4004233.
Methot, J. L., Hoffman, D. M., Witter, D. J., Stanton, M. G., Harrington, P., Hamblett, C., Siliphaivanh, P., Wilson, K., Hubbs, J., Heidebrecht, R., Kral, A. M., Ozerova, N., Fleming, J. C., Wang, H., Szewczak, A. A., Middleton, R. E., Hughes, B., Cruz, J. C., Haines, B. B., Chenard, M., Kenific, C. M., Harsch, A., Secrist, J. P., & Miller, T. A. (2014). Delayed and Prolonged Histone Hyperacetylation with a Selective HDAC1/HDAC2 Inhibitor. ACS medicinal chemistry letters, 5(4), 340-5. https://doi.org/10.1021/ml4004233
Methot, Joey L, et al. "Delayed and Prolonged Histone Hyperacetylation with a Selective HDAC1/HDAC2 Inhibitor." ACS medicinal chemistry letters vol. 5,4 (2014): 340-5. doi: https://doi.org/10.1021/ml4004233
Methot JL, Hoffman DM, Witter DJ, Stanton MG, Harrington P, Hamblett C, Siliphaivanh P, Wilson K, Hubbs J, Heidebrecht R, Kral AM, Ozerova N, Fleming JC, Wang H, Szewczak AA, Middleton RE, Hughes B, Cruz JC, Haines BB, Chenard M, Kenific CM, Harsch A, Secrist JP, Miller TA. Delayed and Prolonged Histone Hyperacetylation with a Selective HDAC1/HDAC2 Inhibitor. ACS Med Chem Lett. 2014 Jan 02;5(4):340-5. doi: 10.1021/ml4004233. eCollection 2014 Apr 10. PMID: 24900838; PMCID: PMC4027730.
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ACS Med Chem Lett. 2014 Jan 02;5(4):340-5. doi: 10.1021/ml4004233. eCollection 2014 Apr 10.

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

ACS medicinal chemistry letters

Joey L Methot, Dawn Mampreian Hoffman, David J Witter, Matthew G Stanton, Paul Harrington, Christopher Hamblett, Phieng Siliphaivanh, Kevin Wilson, Jed Hubbs, Richard Heidebrecht, Astrid M Kral, Nicole Ozerova, Judith C Fleming, Hongmei Wang, Alexander A Szewczak, Richard E Middleton, Bethany Hughes, Jonathan C Cruz, Brian B Haines, Melissa Chenard, Candia M Kenific, Andreas Harsch, J Paul Secrist, Thomas A Miller

Affiliations

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

PMID: 24900838 PMCID: PMC4027730 DOI: 10.1021/ml4004233

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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