title: Identification of highly selective and potent histone deacetylase 3 inhibitors using click chemistry-based combinatorial fragment assembly.
abstract: 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 IC50s, 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.
authors.affiliation: Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan. suzukit@koto.kpu-m.ac.jp
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Suzuki
authors.forename: Yuki
authors.initials: Y
authors.lastname: Kasuya
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Itoh
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Ota
authors.forename: Peng
authors.initials: P
authors.lastname: Zhan
authors.forename: Kaori
authors.initials: K
authors.lastname: Asamitsu
authors.forename: Hidehiko
authors.initials: H
authors.lastname: Nakagawa
authors.forename: Takashi
authors.initials: T
authors.lastname: Okamoto
authors.forename: Naoki
authors.initials: N
authors.lastname: Miyata
mesh_terms: D057930:Click Chemistry / Q000379:methods*; D004353:Drug Evaluation, Preclinical; D045325:HCT116 Cells; D056572:Histone Deacetylase Inhibitors / Q000737:chemistry*; D006655:Histone Deacetylases / Q000187:drug effects*; D006801:Humans; D014230:Triazoles / Q000737:chemistry; D000099186:Histone Deacetylase 3
chemical_list: D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases; D014230:Triazoles; D000099186:Histone Deacetylase 3