Highly potent and selective histone deacetylase 6 inhibitors designed based on a small-molecular substrate.
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.
Suzuki
Takayoshi
T
Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Nagoya, Aichi 467-8603, Japan. suzuki@phar.nagoya-cu.ac.jp
Kouketsu
Akiyasu
A
Itoh
Yukihiro
Y
Hisakawa
Shinya
S
Maeda
Satoko
S
Yoshida
Minoru
M
Nakagawa
Hidehiko
H
Miyata
Naoki
N
D000107:Acetylation; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D045325:HCT116 Cells; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D013329:Structure-Activity Relationship; D013438:Sulfhydryl Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014404:Tubulin / Q000378:metabolism
D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D013438:Sulfhydryl Compounds; D014404:Tubulin