Novel aminophenyl benzamide-type histone deacetylase inhibitors with enhanced potency and selectivity.
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.
Moradei
Oscar M
OM
MethylGene Inc, 7220 Frederick-Banting, Montréal, QC H4S 2A1, Canada. moradeio@methylgene.com
Mallais
Tammy C
TC
Frechette
Sylvie
S
Paquin
Isabelle
I
Tessier
Pierre E
PE
Leit
Silvana M
SM
Fournel
Marielle
M
Bonfils
Claire
C
Trachy-Bourget
Marie-Claude
MC
Liu
Jianhong
J
Yan
Theresa P
TP
Lu
Ai-Hua
AH
Rahil
Jubrail
J
Wang
James
J
Lefebvre
Sylvain
S
Li
Zuomei
Z
Vaisburg
Arkadii F
AF
Besterman
Jeffrey M
JM
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
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