Takayoshi Suzuki

Histone deacetylases (HDACs) catalyze the deacetylation of the acetylated lysine residues of histones and non-histone proteins, and are involved in various fundamental life phenomena, such as gene expression and cell cycle progression. Thus far, eighteen HDAC family members (HDAC1—11 and SIRT1—7) have been identified, but the functions of the HDAC isoforms are not yet fully understood. In addition, some of the HDAC isoforms have been suggested to be associated with various disease states, including cancer and neurodegenerative disorders. Therefore, isoform-selective HDAC inhibitors are of great interest, not only as tools for probing the biological functions of the isoforms, but also as candidate therapeutic agents with few side effects. It was against this background that we initiated research programs to identify isoform-selective HDAC inhibitors. We designed HDAC inhibitors based on the three-dimensional structure of the enzyme and on the proposed catalytic mechanism of HDACs, and found several isoform-selective HDAC inhibitors. Furthermore, we elucidated the functions of HDAC6 by chemical genetic approaches using these inhibitors. The results of this research also suggested the feasibility of using isoform-selective HDAC inhibitors as therapeutic agents.

To find novel histone deacetylase 6 (HDAC6)-selective inhibitors and clarify the structural requirements for HDAC6-selective inhibition, we prepared thiolate analogues designed based on the structure of an HDAC6-selective substrate and evaluated the histone/alpha-tubulin acetylation selectivity by Western blot analysis. Aliphatic compounds 17b-20b selectively caused alpha-tubulin acetylation over histone H4 acetylation. In enzyme assays using HDAC1, HDAC4, and HDAC6, compounds 17a-19a exhibited HDAC6-selective inhibition over HDAC1 and HDAC4.

While most inhibitors of histone deacetylases (HDACs) are hydroxamic acid derivatives, several nonhydroxamates have recently been developed as inhibitors and attracted quite a deal of attention. In this review, we present the rational design, inhibitory effect and antiproliferative activity of non-hydroxamate HDAC inhibitors.

A number of histone deacetylase (HDAC) inhibitors have been developed as anticancer agents and most of them are hydroxamic acid derivatives, typified by suberoylanilide hydroxamic acid (SAHA), Trichostatin A (TSA) and NVP-LAQ824. However, hydroxamic acids have been associated with poor pharmacokinetics and severe toxicity. In addition, although isozyme-selective HDAC inhibitors are considered useful not only as tools for probing the biology of an enzyme but as drugs with low toxicity, many of the hydroxamate HDAC inhibitors do not distinguish well among the HDAC isozymes. Thus, there has been considerable interest in developing non-hydroxamate HDAC inhibitors. To date, small fatty acids, oaminoanilides, electrophilic ketones, N-formyl hydroxylamines, thiols and mercaptoamides have been reported as non-hydroxamate HDAC inhibitors, and some of them show antiproliferative activity comparable to hydroxamates. Interestingly, hydroxamate HDAC inhibitors such as SAHA and TSA do not discriminate well among the HDAC isozymes whereas many non-hydroxamate HDAC inhibitors have shown selectivity. These non-hydroxamate HDAC inhibitors should pave the way for the development of tools for biological research and new medicines with few side effects. In this review, we introduce non-hydroxamate HDAC inhibitors describing their design, enzyme inhibition, cancer cell growth inhibition and isozyme selectivity.