2. Academic Validation
  3. Isoindoline scaffold-based dual inhibitors of HDAC6 and HSP90 suppressing the growth of lung cancer in vitro and in vivo

Isoindoline scaffold-based dual inhibitors of HDAC6 and HSP90 suppressing the growth of lung cancer in vitro and in vivo

  • Eur J Med Chem. 2020 Mar 15;190:112086. doi: 10.1016/j.ejmech.2020.112086.
Ritu Ojha 1,  Kunal Nepali 1,  Chun-Han Chen 2,  Kuo-Hsiang Chuang 3,  Tung-Yun Wu 4,  Tony Eight Lin 5,  Kai-Cheng Hsu 5,  Min-Wu Chao 5,  Mei-Jung Lai 6,  Mei-Hsiang Lin 1,  Han-Li Huang 6,  Chao-Di Chang 7,  Shiow-Lin Pan 8,  Mei-Chuan Chen 9,  Jing-Ping Liou 10
Affiliations

Affiliations

  • 1 School of Pharmacy, College of Pharmacy, Taipei Medical University, Taiwan.
  • 2 Department of Pharmacology, School of Medicine, College of Medicine, Taipei Medical University, Taiwan.
  • 3 Graduate Institute of Pharmacognosy, Taipei Medical University, Taiwan; Clinical Drug Development of Herbal Medicine, College of Pharmacy, Taipei Medical University, Taiwan.
  • 4 Clinical Drug Development of Herbal Medicine, College of Pharmacy, Taipei Medical University, Taiwan.
  • 5 Graduate Institute of Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taiwan.
  • 6 TMU Biomedical Commercialization Center, Taipei Medical University, Taiwan.
  • 7 Biotechnology Research and Development, College of Pharmacy, Taipei Medical University, Taiwan.
  • 8 Graduate Institute of Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taiwan; Biotechnology Research and Development, College of Pharmacy, Taipei Medical University, Taiwan.
  • 9 Clinical Drug Development of Herbal Medicine, College of Pharmacy, Taipei Medical University, Taiwan; Traditional Herbal Medicine Research Center of Taipei Medical University Hospital, Taipei, 11031, Taiwan. Electronic address: mcchen1250@tmu.edu.tw.
  • 10 School of Pharmacy, College of Pharmacy, Taipei Medical University, Taiwan; TMU Biomedical Commercialization Center, Taipei Medical University, Taiwan; Biotechnology Research and Development, College of Pharmacy, Taipei Medical University, Taiwan. Electronic address: jpl@tmu.edu.tw.
PMID: 32058238 DOI: 10.1016/j.ejmech.2020.112086
Abstract

This study reports the synthesis of a series of 2-aroylisoindoline hydroxamic acids employing N-benzyl, long alkyl chain and acrylamide units as diverse linkers. In-vitro studies led to the identification of N-benzyl linker-bearing compound (10) and long chain linker-containing compound (17) as dual selective HDAC6/HSP90 inhibitors. Compound 17 displays potent inhibition of HDAC6 isoform (IC50 = 4.3 nM) and HSP90a inhibition (IC50 = 46.8 nM) along with substantial cell growth inhibitory effects with GI50 = 0.76 μM (lung A549) and GI50 = 0.52 μM (lung EGFR resistant H1975). Compound 10 displays potent antiproliferative activity against lung A549 (GI50 = 0.37 μM) and lung H1975 cell lines (GI50 = 0.13 μM) mediated through selective HDAC6 inhibition (IC50 = 33.3 nM) and HSP90 inhibition (IC50 = 66 nM). In addition, compound 17 also modulated the expression of signatory biomarkers associated with HDAC6 and HSP90 inhibition. In the in vivo efficacy evaluation in human H1975 xenografts, 17 induced slightly remarkable suppression of tumor growth both in monotherapy as well as the combination therapy with afatinib (20 mg/kg). Moreover, compound 17 could effectively reduce programmed death-ligand 1 (PD-L1) expression in IFN-γ treated lung H1975 cells in a dose dependent manner suggesting that dual inhibition of HDAC6 and HSP90 can modulate immunosuppressive ability of tumor area.

Keywords

Heat shock protein; Histone deacetylase; Isoindoline; Lung cancer; Programmed death-ligand 1 (PD-L1).

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