title: Delayed and Prolonged Histone Hyperacetylation with a Selective HDAC1/HDAC2 Inhibitor.
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.
authors.affiliation: Merck Research Laboratories , 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.
authors.forename: Joey L
authors.initials: JL
authors.lastname: Methot
authors.affiliation: Merck Research Laboratories , 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.
authors.forename: Dawn Mampreian
authors.initials: DM
authors.lastname: Hoffman
authors.affiliation: Merck Research Laboratories , 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.
authors.forename: David J
authors.initials: DJ
authors.lastname: Witter
authors.affiliation: Merck Research Laboratories , 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.
authors.forename: Matthew G
authors.initials: MG
authors.lastname: Stanton
authors.affiliation: Merck Research Laboratories , 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.
authors.forename: Paul
authors.initials: P
authors.lastname: Harrington
authors.affiliation: Merck Research Laboratories , 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.
authors.forename: Christopher
authors.initials: C
authors.lastname: Hamblett
authors.affiliation: Merck Research Laboratories , 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.
authors.forename: Phieng
authors.initials: P
authors.lastname: Siliphaivanh
authors.affiliation: Merck Research Laboratories , 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.
authors.forename: Kevin
authors.initials: K
authors.lastname: Wilson
authors.affiliation: Merck Research Laboratories , 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.
authors.forename: Jed
authors.initials: J
authors.lastname: Hubbs
authors.affiliation: Merck Research Laboratories , 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.
authors.forename: Richard
authors.initials: R
authors.lastname: Heidebrecht
authors.affiliation: Merck Research Laboratories , 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.
authors.forename: Astrid M
authors.initials: AM
authors.lastname: Kral
authors.affiliation: Merck Research Laboratories , 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.
authors.forename: Nicole
authors.initials: N
authors.lastname: Ozerova
authors.affiliation: Merck Research Laboratories , 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.
authors.forename: Judith C
authors.initials: JC
authors.lastname: Fleming
authors.affiliation: Merck Research Laboratories , 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.
authors.forename: Hongmei
authors.initials: H
authors.lastname: Wang
authors.affiliation: Merck Research Laboratories , 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.
authors.forename: Alexander A
authors.initials: AA
authors.lastname: Szewczak
authors.affiliation: Merck Research Laboratories , 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.
authors.forename: Richard E
authors.initials: RE
authors.lastname: Middleton
authors.affiliation: Merck Research Laboratories , 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.
authors.forename: Bethany
authors.initials: B
authors.lastname: Hughes
authors.affiliation: Merck Research Laboratories , 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Cruz
authors.affiliation: Merck Research Laboratories , 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.
authors.forename: Brian B
authors.initials: BB
authors.lastname: Haines
authors.affiliation: Merck Research Laboratories , 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.
authors.forename: Melissa
authors.initials: M
authors.lastname: Chenard
authors.affiliation: Merck Research Laboratories , 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.
authors.forename: Candia M
authors.initials: CM
authors.lastname: Kenific
authors.affiliation: Merck Research Laboratories , 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.
authors.forename: Andreas
authors.initials: A
authors.lastname: Harsch
authors.affiliation: Merck Research Laboratories , 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.
authors.forename: J Paul
authors.initials: JP
authors.lastname: Secrist
authors.affiliation: Merck Research Laboratories , 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Miller
keywords: Histone acetylation; histone deacetylase inhibitor; isoform selectivity; kinetics