Identification of Novel Histone Deacetylase 6-Selective Inhibitors Bearing 3,3,3-Trifluorolactic Amide (TFLAM) Motif as a Zinc Binding Group

Takashi Kurohara, Keita Tanaka, Daisuke Takahashi, Satoshi Ueda, Yasunobu Yamashita, Yuri Takada, Hirokazu Takeshima, Shengwang Yu, Yukihiro Itoh, Koji Hase, Takayoshi Suzuki

Research output: Contribution to journalArticlepeer-review

Abstract

Pharmacological inhibition of histone deacetylase 6 (HDAC6) is an effective therapeutic strategy for cancer and immunological diseases. Most of the previously reported HDAC6 inhibitors have a hydroxamate group as a zinc binding group (ZBG), which coordinates to the catalytic zinc ion of HDAC6. The hydroxamate group is liable to metabolically generate mutagenetic hydroxylamine; therefore, non-hydroxamate HDAC6 inhibitors would be advantageous. In this study, to identify novel non-hydroxamate HDAC6-selective inhibitors, screening of a chemical library and the subsequent structural optimization were performed, which led to the identification of HDAC6-selective inhibitors with 3,3,3-trifluorolactic amide (TFLAM) as a novel ZBG. The identified inhibitor showed potent and selective HDAC6-inhibitory activity in cells and induced regulatory T (Treg) cell differentiation.

Original languageEnglish
JournalChemBioChem
DOIs
Publication statusAccepted/In press - 2021

Keywords

  • drug discovery
  • fluorine
  • HDAC6
  • medicinal chemistry

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Organic Chemistry

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