2. Academic Validation
  3. N-alkyl-hydroxybenzoyl anilide hydroxamates as dual inhibitors of HDAC and HSP90, downregulating IFN-γ induced PD-L1 expression

N-alkyl-hydroxybenzoyl anilide hydroxamates as dual inhibitors of HDAC and HSP90, downregulating IFN-γ induced PD-L1 expression

  • Eur J Med Chem. 2020 Jan 1;185:111725. doi: 10.1016/j.ejmech.2019.111725.
Samir Mehndiratta 1,  Mei-Hsiang Lin 1,  Yi-Wen Wu 2,  Chun-Han Chen 3,  Tung-Yun Wu 4,  Kuo-Hsiang Chuang 5,  Min-Wu Chao 6,  Yi-Ying Chen 6,  Shiow-Lin Pan 6,  Mei-Chuan Chen 7,  Jing-Ping Liou 8
Affiliations

Affiliations

  • 1 School of Pharmacy, College of Pharmacy, Taipei Medical University, Taiwan.
  • 2 PhD Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taiwan.
  • 3 Department of Pharmacology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
  • 4 Ph.D. Program for the Clinical Drug Discovery from Botanical Herbs, College of Pharmacy, Taipei Medical University, Taipei, Taiwan.
  • 5 Graduate Institute of Pharmacognosy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan; Ph.D. Program for the Clinical Drug Discovery from Botanical Herbs, College of Pharmacy, Taipei Medical University, Taipei, Taiwan.
  • 6 Graduate Institute of Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
  • 7 Ph.D. Program for the Clinical Drug Discovery from Botanical Herbs, College of Pharmacy, Taipei Medical University, Taipei, Taiwan. Electronic address: mcchen1250@tmu.edu.tw.
  • 8 School of Pharmacy, College of Pharmacy, Taipei Medical University, Taiwan; School of Pharmacy, National Defense Medical Center, Taipei, Taiwan; TMU Biomedical Commercialization Center, Taipei Medical University, Taiwan. Electronic address: jpl@tmu.edu.tw.
PMID: 31655430 DOI: 10.1016/j.ejmech.2019.111725
Abstract

Novel dual inhibitors of histone deacetylase (HDAC) and heat-shock protein 90 (HSP90) are synthesized and evaluated. These compounds are endowed with potent HDAC and HSP90 inhibitory activities with IC50 values in nanomolar range with Compound 20 (HDAC IC50 = 194 nM; HSP90α IC50 = 153 nM) and compound 26 (HDAC IC50 = 360 nM; HSP90α IC50 = 77 nM) displaying most potent HDAC and HSP90α inhibitory activities. Both of these compounds induce HSP70 expression and down regulate HSP90 client proteins which play important roles in the regulation of survival and invasiveness in Cancer cells. In addition, compounds 20 and 26 induce acetylation of α-tubulin and histone H3. Significantly, compounds 20 and 26 could effectively reduce programmed death-ligand 1 (PD-L1) expression in IFN-γ treated lung H1975 cells in a dose dependent manner. These findings suggest that dual inhibition of HDAC and HSP90 that can modulate immunosuppressive ability of tumor area may provide a better therapeutic strategy for Cancer treatment in the future.

Keywords

Design multiple ligand; Dual inhibitors; Heat shock protein; Histone deacetylase inhibitors; Lung cancer; Programmed death-ligand 1 (PD-L1).

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