Identification of a potent non-hydroxamate histone deacetylase inhibitor by mechanism-based drug design.
In order to find novel non-hydroxamate histone deacetylase (HDAC) inhibitors, we synthesized several suberoylanilide hydroxamic acid (SAHA)-based compounds designed on the basis of the catalytic mechanism of HDACs. Among these compounds, 5b was found to be as potent as SAHA. Kinetic enzyme assays and molecular modeling suggested that the mercaptoacetamide moiety of 5b interacts with the zinc in the active site of HDACs and removes a water molecule from the reactive site of the deacetylation.
Suzuki
Takayoshi
T
Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya, Aichi 467-8603, Japan. suzuki@phar.nagoya-cu.ac.jp
Matsuura
Azusa
A
Kouketsu
Akiyasu
A
Nakagawa
Hidehiko
H
Miyata
Naoki
N
D000081:Acetamides / Q000737:chemistry; D000107:Acetylation; D001665:Binding Sites; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids / Q000138:chemical synthesis* / Q000494:pharmacology; D007700:Kinetics; D008958:Models, Molecular; D013329:Structure-Activity Relationship; D013438:Sulfhydryl Compounds / Q000737:chemistry; D000077337:Vorinostat; D015032:Zinc / Q000737:chemistry
D000081:Acetamides; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D013438:Sulfhydryl Compounds; D000077337:Vorinostat; C030686:acetamide; D015032:Zinc