Identification of a potent non-hydroxamate histone deacetylase inhibitor by mechanism-based drug design

Takayoshi Suzuki; Azusa Matsuura; Akiyasu Kouketsu; Hidehiko Nakagawa; Naoki Miyata

doi:10.1016/j.bmcl.2004.10.074

Identification of a potent non-hydroxamate histone deacetylase inhibitor by mechanism-based drug design

Bioorg Med Chem Lett. 2005 Jan 17;15(2):331-5. doi: 10.1016/j.bmcl.2004.10.074.

Authors

Takayoshi Suzuki¹, Azusa Matsuura, Akiyasu Kouketsu, Hidehiko Nakagawa, Naoki Miyata

Affiliation

¹ 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

PMID: 15603949
DOI: 10.1016/j.bmcl.2004.10.074

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acetamides / chemistry
Acetylation
Binding Sites
Enzyme Inhibitors / chemical synthesis*
Enzyme Inhibitors / pharmacology
Histone Deacetylase Inhibitors*
Hydroxamic Acids / chemical synthesis*
Hydroxamic Acids / pharmacology
Kinetics
Models, Molecular
Structure-Activity Relationship
Sulfhydryl Compounds / chemistry
Vorinostat
Zinc / chemistry

Substances

Acetamides
Enzyme Inhibitors
Histone Deacetylase Inhibitors
Hydroxamic Acids
Sulfhydryl Compounds
Vorinostat
acetamide
Zinc