2. Academic Validation
  3. Discovery of Selective Histone Deacetylase 1 and 2 Inhibitors: Screening of a Focused Library Constructed by Click Chemistry, Kinetic Binding Analysis, and Biological Evaluation

Discovery of Selective Histone Deacetylase 1 and 2 Inhibitors: Screening of a Focused Library Constructed by Click Chemistry, Kinetic Binding Analysis, and Biological Evaluation

  • J Med Chem. 2023 Oct 17. doi: 10.1021/acs.jmedchem.3c01095.
Yukihiro Itoh 1 2,  Peng Zhan 2,  Toshifumi Tojo 2,  Pattaporn Jaikhan 2,  Yosuke Ota 2,  Miki Suzuki 2,  Ying Li 2,  Zi Hui 2,  Yukiko Moriyama 1,  Yuri Takada 1,  Yasunobu Yamashita 1,  Makoto Oba 2,  Shusaku Uchida 3,  Mitsuharu Masuda 4,  Shinji Ito 5,  Yoshihiro Sowa 4,  Toshiyuki Sakai 4,  Takayoshi Suzuki 1 2
Affiliations

Affiliations

  • 1 SANKEN, Osaka University, 8-1 Mihogaoka, Ibaraki, Osaka 567-0047, Japan.
  • 2 Department of Chemistry, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 1-5 Shimogamohangi-cho, Sakyo-ku, Kyoto 606-0823, Japan.
  • 3 SK Project, Medical Innovation Center, Kyoto University Graduate School of Medicine, 53 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan.
  • 4 Department of Molecular-Targeting Cancer Prevention, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan.
  • 5 Medical Research Support Center, Graduate School of Medicine, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan.
PMID: 37847303 DOI: 10.1021/acs.jmedchem.3c01095
Abstract

Histone deacetylase 1 and 2 (HDAC1/2) inhibitors are potentially useful as tools for probing the biological functions of the isoforms and as therapeutic agents for Cancer and neurodegenerative disorders. To discover potent and selective inhibitors, we screened a focused library synthesized by using Click Chemistry and obtained KPZ560 as an HDAC1/2-selective inhibitor. Kinetic binding analysis revealed that KPZ560 inhibits HDAC2 through a two-step slow-binding mechanism. In cellular assays, KPZ560 induced a dose- and time-dependent increase of histone acetylation and showed potent breast Cancer cell growth-inhibitory activity. In addition, gene expression analyses suggested that the two-step slow-binding inhibition by KPZ560 regulated the expression of genes associated with cell proliferation and DNA damage. KPZ560 also induced neurite outgrowth of Neuro-2a cells and an increase in the spine density of granule neuron dendrites of mice. The unique two-step slow-binding character of o-aminoanilides such as KPZ560 makes them interesting candidates as therapeutic agents.

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