Explorative Study on Isoform-Selective Histone Deacetylase Inhibitors

Abstract

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.

Valproic acid, a histone deacetylase inhibitor, enhances radiosensitivity in esophageal squamous cell carcinoma

“…A currently held idea proposes a classification according to isoform-selective HDAC inhibition in probing for biological functions. A novel isoformselective HDAC inhibitor will be useful in elucidating the mechanism of action and the development of therapeutic agents with minimal side-effects (48).…”

HDAC6 α-tubulin deacetylase: A potential therapeutic target in neurodegenerative diseases

“…Itoh [9,75], Suzuki [82,84] and their respective colleagues synthesized a set of different thiol-containing analogs based on small-molecule HDAC6-selective substrates [85]: NCT-10a, NCT-14a, and S-isobutyryl prodrugs NCT-10b and NCT-14b [9,84]. NCT-10a (EC50 = 29 nM) and NCT-14a (EC50 = 82 μM) show high selectivity for HDAC6 over HDAC1 and HDAC4 in enzyme assays [75,82].…”

Aurones as histone deacetylase inhibitors: Identification of key features

“…5 The general HDACi pharmacophore consists of three distinct structural parts: the zinc-binding group that chelates a zinc residue within the active site, the recognition cap group responsible for HDAC subtype selectivity and a hydrophobic linker which links these 2 groups. 6,7 The first discovered HDACi are from natural sources. Some of them are very potent such as trichostatin A 8 and have been studied in the context of cancer therapy.…”