Delayed and Prolonged Histone Hyperacetylation with a Selective HDAC1/HDAC2 Inhibitor.
Basic Information
ID: ALA3286368
Journal: ACS Med Chem Lett
Title: Delayed and Prolonged Histone Hyperacetylation with a Selective HDAC1/HDAC2 Inhibitor.
Authors: 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.
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.
CiteXplore: 24900838
DOI: 10.1021/ml4004233
Patent ID: ┄