期刊
CHEMICAL & PHARMACEUTICAL BULLETIN
卷 57, 期 9, 页码 897-906出版社
PHARMACEUTICAL SOC JAPAN
DOI: 10.1248/cpb.57.897
关键词
histone deacetylase; isoform-selective inhibitor; chemical genetic approach
资金
- Ministry of Education, Culture, Sports, Science and Technology of Japan
- Mochida Memorial Foundation for Medical and Pharmaceutical Research
- Hori Information Science Promotion Foundation
- Japan Securities Scholarship Foundation
- Tokyo Biochemical Research Foundation
- Takeda Science Foundation
- Ichihara International Scholarship Foundation
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.
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