2. Academic Validation
  3. Discovery of aliphatic-chain hydroxamates containing indole derivatives with potent class I histone deacetylase inhibitory activities

Discovery of aliphatic-chain hydroxamates containing indole derivatives with potent class I histone deacetylase inhibitory activities

  • Eur J Med Chem. 2018 Jan 1:143:792-805. doi: 10.1016/j.ejmech.2017.11.092.
Shi-Wei Chao 1,  Liang-Chieh Chen 1,  Chia-Chun Yu 2,  Chang-Yi Liu 3,  Tony Eight Lin 3,  Jih-Hwa Guh 2,  Chen-Yu Wang 4,  Chun-Yung Chen 5,  Kai-Cheng Hsu 6,  Wei-Jan Huang 7
Affiliations

Affiliations

  • 1 School of Pharmacy, Taipei Medical University, Taipei, Taiwan; Graduate Institute of Pharmacognosy, Taipei Medical University, Taipei, Taiwan.
  • 2 School of Pharmacy, National Taiwan University, Taipei, Taiwan.
  • 3 Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
  • 4 TaiMed Biologics Inc., Taipei, Taiwan.
  • 5 Graduate Institute of Pharmacognosy, Taipei Medical University, Taipei, Taiwan.
  • 6 Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan. Electronic address: piki@tmu.edu.tw.
  • 7 Graduate Institute of Pharmacognosy, Taipei Medical University, Taipei, Taiwan; School of Pharmacy, National Defense Medical Center, Taipei, Taiwan; Ph.D. Program for the Clinical Drug Discovery from Botanical Herbs, Taipei Medical University, Taipei, Taiwan; Ph.D. Program in Biotechnology Research and Development, College of Pharmacy, Taipei Medical University, Taipei, Taiwan. Electronic address: wjhuang@tmu.edu.tw.
PMID: 29223096 DOI: 10.1016/j.ejmech.2017.11.092
Abstract

Histone deacetylase (HDAC) is a validated drug target for various diseases. This study combined indole recognition cap with SAHA, an FDA-approved HDAC Inhibitor used to treat cutaneous T-cell lymphoma (CTCL). The structure activity relationship of the resulting compounds that inhibited HDAC was disclosed as well. Some compounds exhibited much stronger inhibitory activities than SAHA. We identified two meta-series compounds 6j and 6k with a two-carbon linker had IC50 values of 3.9 and 4.5 nM for HDAC1, respectively. In contrast, the same oriented compounds with longer carbon chain linkers showed weaker inhibition. The result suggests that the linker chain length greatly contributed to Enzyme inhibitory potency. In addition, comparison of enzyme-inhibiting activity between the compounds and SAHA showed that compounds 6j and 6k displayed higher inhibiting activity for class I (HDAC1, -2, -3 and -8). The molecular docking and structure analysis revealed structural differences with the inhibitor cap and metal-binding regions between the HDAC isozymes that affect interactions with the inhibitors and play a key role for selectivity. Further biological evaluation showed multiple cellular effects associated with compounds 6j- and 6k-induced HDAC inhibitory activity.

Keywords

Histone deacetylase; Indole; Isozyme; Molecular docking; Structure activity relationship.

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