title: Novel aminophenyl benzamide-type histone deacetylase inhibitors with enhanced potency and selectivity.
abstract: Significant effort is being made to understand the role of HDAC isotypes in human cancer and to develop antitumor agents with better therapeutic windows. A part of this endeavor was the exploration of the 14 A internal cavity adjacent to the enzyme catalytic site, which led to the design and synthesis of compound 4 with the unusual bis(aryl)-type pharmacophore. SAR studies around this lead resulted in optimization to potent, selective, nonhydroxamic acid HDAC inhibitors.
authors.affiliation: MethylGene Inc, 7220 Frederick-Banting, Montréal, QC H4S 2A1, Canada. moradeio@methylgene.com
authors.forename: Oscar M
authors.initials: OM
authors.lastname: Moradei
authors.forename: Tammy C
authors.initials: TC
authors.lastname: Mallais
authors.forename: Sylvie
authors.initials: S
authors.lastname: Frechette
authors.forename: Isabelle
authors.initials: I
authors.lastname: Paquin
authors.forename: Pierre E
authors.initials: PE
authors.lastname: Tessier
authors.forename: Silvana M
authors.initials: SM
authors.lastname: Leit
authors.forename: Marielle
authors.initials: M
authors.lastname: Fournel
authors.forename: Claire
authors.initials: C
authors.lastname: Bonfils
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Trachy-Bourget
authors.forename: Jianhong
authors.initials: J
authors.lastname: Liu
authors.forename: Theresa P
authors.initials: TP
authors.lastname: Yan
authors.forename: Ai-Hua
authors.initials: AH
authors.lastname: Lu
authors.forename: Jubrail
authors.initials: J
authors.lastname: Rahil
authors.forename: James
authors.initials: J
authors.lastname: Wang
authors.forename: Sylvain
authors.initials: S
authors.lastname: Lefebvre
authors.forename: Zuomei
authors.initials: Z
authors.lastname: Li
authors.forename: Arkadii F
authors.initials: AF
authors.lastname: Vaisburg
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Besterman
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry; D001549:Benzamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D020134:Catalytic Domain; D002460:Cell Line; D056284:Histone Deacetylase 1; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D009247:NADH, NADPH Oxidoreductases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D056572:Histone Deacetylase Inhibitors; D009247:NADH, NADPH Oxidoreductases; C058515:8-hydroxy-5-deazaflavin-NADPH oxidoreductase; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases