title: Phenylglycine and phenylalanine derivatives as potent and selective HDAC1 inhibitors (SHI-1).
abstract: An HTS screening campaign identified a series of low molecular weight phenols that showed excellent selectivity (>100-fold) for HDAC1/HDAC2 over other Class I and Class II HDACs. Evolution and optimization of this HTS hit series provided HDAC1-selective (SHI-1) compounds with excellent anti-proliferative activity and improved physical properties. Dose-dependent efficacy in a mouse HCT116 xenograft model was demonstrated with a phenylglycine SHI-1 analog.
authors.affiliation: Department of Drug Design and Optimization, Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA. kevin_wilson2@merck.com
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Wilson
authors.forename: David J
authors.initials: DJ
authors.lastname: Witter
authors.forename: Jonathan B
authors.initials: JB
authors.lastname: Grimm
authors.forename: Phieng
authors.initials: P
authors.lastname: Siliphaivanh
authors.forename: Karin M
authors.initials: KM
authors.lastname: Otte
authors.forename: Astrid M
authors.initials: AM
authors.lastname: Kral
authors.forename: Judith C
authors.initials: JC
authors.lastname: Fleming
authors.forename: Andreas
authors.initials: A
authors.lastname: Harsch
authors.forename: Julie E
authors.initials: JE
authors.lastname: Hamill
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Cruz
authors.forename: Melissa
authors.initials: M
authors.lastname: Chenard
authors.forename: Alexander A
authors.initials: AA
authors.lastname: Szewczak
authors.forename: Richard E
authors.initials: RE
authors.lastname: Middleton
authors.forename: Bethany L
authors.initials: BL
authors.lastname: Hughes
authors.forename: William K
authors.initials: WK
authors.lastname: Dahlberg
authors.forename: J Paul
authors.initials: JP
authors.lastname: Secrist
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Miller
mesh_terms: D000107:Acetylation; D000577:Amides; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects*; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D004285:Dogs; D000072237:ERG1 Potassium Channel; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D051638:Ether-A-Go-Go Potassium Channels / Q000378:metabolism; D005998:Glycine / Q000031:analogs & derivatives* / Q000737:chemistry; D056284:Histone Deacetylase 1; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D008253:Macaca mulatta; D051379:Mice; D015394:Molecular Structure; D010649:Phenylalanine / Q000737:chemistry*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000577:Amides; D000072237:ERG1 Potassium Channel; D004791:Enzyme Inhibitors; D051638:Ether-A-Go-Go Potassium Channels; D056572:Histone Deacetylase Inhibitors; C027797:phenylglycine chloride; D010649:Phenylalanine; C110550:HDAC1 protein, human; C484389:Hdac1 protein, mouse; D056284:Histone Deacetylase 1; D005998:Glycine