Open AccessIdentification of Highly Selective and Potent Histone Deacetylase 3 Inhibitors Using Click Chemistry-Based Combinatorial Fragment Assembly
Author(s) -
Takayoshi Suzuki,
Yuki Kasuya,
Yukihiro Itoh,
Yosuke Ota,
Peng Zhan,
Kaori Asamitsu,
Hidehiko Nakagawa,
Takashi Okamoto,
Naoki Miyata
Publication year - 2013
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0068669
Subject(s) - hdac3 , click chemistry , histone deacetylase , isozyme , chemistry , acetylation , triazole , biochemistry , hdac6 , hdac1 , histone , enzyme , combinatorial chemistry , gene , organic chemistry
To find histone deacetylase 3 (HDAC3)-selective inhibitors, a series of 504 candidates was assembled using “click chemistry”, by reacting nine alkynes bearing a zinc-binding group with 56 azide building blocks in the presence of Cu(I) catalyst. Screening of the 504-member triazole library against HDAC3 and other HDAC isozymes led to the identification of potent and selective HDAC3 inhibitors T247 and T326 . These compounds showed potent HDAC3 inhibition with submicromolar IC 50 s, whereas they did not strongly inhibit other isozymes. Compounds T247 and T326 also induced a dose-dependent selective increase of NF-κB acetylation in human colon cancer HCT116 cells, indicating selective inhibition of HDAC3 in the cells. In addition, these HDAC3-selective inhibitors induced growth inhibition of cancer cells, and activated HIV gene expression in latent HIV-infected cells. These findings indicate that HDAC3-selective inhibitors are promising candidates for anticancer drugs and antiviral agents. This work also suggests the usefulness of the click chemistry approach to find isozyme-selective HDAC inhibitors.