title: Exploration of the internal cavity of histone deacetylase (HDAC) with selective HDAC1/HDAC2 inhibitors (SHI-1:2).
abstract: We report herein the initial exploration of novel selective HDAC1/HDAC2 inhibitors (SHI-1:2). Optimized SHI-1:2 structures exhibit enhanced intrinsic activity against HDAC1 and HDAC2, and are greater than 100-fold selective versus other HDACs, including HDAC3. Based on the SAR of these agents and our current understanding of the HDAC active site, we postulate that the SHI-1:2 extend the existing HDAC inhibitor pharmacophore to include an internal binding domain.
authors.affiliation: Department of Drug Design and Optimization, Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA. joey_methot@merck.com
authors.forename: Joey L
authors.initials: JL
authors.lastname: Methot
authors.forename: Prasun K
authors.initials: PK
authors.lastname: Chakravarty
authors.forename: Melissa
authors.initials: M
authors.lastname: Chenard
authors.forename: Joshua
authors.initials: J
authors.lastname: Close
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Cruz
authors.forename: William K
authors.initials: WK
authors.lastname: Dahlberg
authors.forename: Judith
authors.initials: J
authors.lastname: Fleming
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Hamblett
authors.forename: Julie E
authors.initials: JE
authors.lastname: Hamill
authors.forename: Paul
authors.initials: P
authors.lastname: Harrington
authors.forename: Andreas
authors.initials: A
authors.lastname: Harsch
authors.forename: Richard
authors.initials: R
authors.lastname: Heidebrecht
authors.forename: Bethany
authors.initials: B
authors.lastname: Hughes
authors.forename: Joon
authors.initials: J
authors.lastname: Jung
authors.forename: Candia M
authors.initials: CM
authors.lastname: Kenific
authors.forename: Astrid M
authors.initials: AM
authors.lastname: Kral
authors.forename: Peter T
authors.initials: PT
authors.lastname: Meinke
authors.forename: Richard E
authors.initials: RE
authors.lastname: Middleton
authors.forename: Nicole
authors.initials: N
authors.lastname: Ozerova
authors.forename: David L
authors.initials: DL
authors.lastname: Sloman
authors.forename: Matthew G
authors.initials: MG
authors.lastname: Stanton
authors.forename: Alexander A
authors.initials: AA
authors.lastname: Szewczak
authors.forename: Sriram
authors.initials: S
authors.lastname: Tyagarajan
authors.forename: David J
authors.initials: DJ
authors.lastname: Witter
authors.forename: J Paul
authors.initials: JP
authors.lastname: Secrist
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Miller
mesh_terms: D001555:Benzene Derivatives / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites / Q000187:drug effects; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D020033:Protein Isoforms; D012097:Repressor Proteins; D013329:Structure-Activity Relationship
chemical_list: D001555:Benzene Derivatives; D056572:Histone Deacetylase Inhibitors; D020033:Protein Isoforms; D012097:Repressor Proteins; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2; D006655:Histone Deacetylases