2. Academic Validation
  3. Fluoropyrimidin-2,4-dihydroxy-5-isopropylbenzamides as antitumor agents against CRC and NSCLC cancer cells

Fluoropyrimidin-2,4-dihydroxy-5-isopropylbenzamides as antitumor agents against CRC and NSCLC cancer cells

  • Eur J Med Chem. 2020 Oct 1;203:112540. doi: 10.1016/j.ejmech.2020.112540.
Wei-Cheng Wu 1,  Yi-Min Liu 2,  Yu-Hsuan Liao 3,  Kai-Cheng Hsu 4,  Ssu-Ting Lien 5,  I-Chung Chen 1,  Mei-Jung Lai 6,  Yu-Hsuan Li 1,  Shiow-Lin Pan 7,  Mei-Chuan Chen 8,  Jing-Ping Liou 9
Affiliations

Affiliations

  • 1 School of Pharmacy, College of Pharmacy, Taipei Medical University, Taiwan.
  • 2 School of Pharmacy, College of Pharmacy, Taipei Medical University, Taiwan; TMU Biomedical Commercialization Center, Taipei Medical University, Taiwan; Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.
  • 3 Ph.D. Program in Clinical Drug Development of Herbal Medicine, College of Pharmacy, Taipei Medical University, Taiwan.
  • 4 TMU Biomedical Commercialization Center, Taipei Medical University, Taiwan; Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
  • 5 Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
  • 6 TMU Biomedical Commercialization Center, Taipei Medical University, Taiwan.
  • 7 School of Pharmacy, College of Pharmacy, Taipei Medical University, Taiwan; TMU Biomedical Commercialization Center, Taipei Medical University, Taiwan; Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
  • 8 School of Pharmacy, College of Pharmacy, Taipei Medical University, Taiwan; Traditional Herbal Medicine Research Center of Taipei Medical University Hospital, Taipei, Taiwan; Ph.D. Program in Clinical Drug Development of Herbal Medicine, College of Pharmacy, Taipei Medical University, Taiwan. Electronic address: [email protected].
  • 9 School of Pharmacy, College of Pharmacy, Taipei Medical University, Taiwan; TMU Biomedical Commercialization Center, Taipei Medical University, Taiwan. Electronic address: [email protected].
PMID: 32683166 DOI: 10.1016/j.ejmech.2020.112540
Abstract

A major cause of failure of therapy in patients with non-small cell lung Cancer (NSCLC) is development of acquired drug resistance leading to tumor recurrence and disease progression. In addition to the development of new generations of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), different molecular targets may provide opportunities to improve the therapeutic outcomes. In this study, we utilized the core structure 5-fluorouracil (5-FU) or tegafur, a 5-FU prodrug combined through different linkers with resorcinol to generate a series of fluoropyrimidin-2,4-dihydroxy-5-isopropylbenzamides which inhibit potent Heat Shock Protein 90 (HSP90). These compounds were found to show significant antiproliferative activity in colorectal Cancer (CRC) HCT116 and NSCLC A549, H460, and H1975 (EGFR L858R/T790 M double mutation) cells. Compound 12c, developed by molecular docking analysis and enzymatic assays exhibits promising inhibitory activity of HSP90. This compound, 12c shows the most potent HSP90 inhibitory activity with an IC50 value of 27.8 ± 4.4 nM, superior to that of reference compounds AUY-922 (Luminespib) and BIIB021 whose IC50 values are 43.0 ± 0.9 nM and 56.8 ± 4.0 nM respectively. This strong HSP90 inhibitory activity of 12c leads to rapid degradation of client proteins EGFR and Akt in NSCLC cells. In addition, 12c induces significant accumulation of a sub-G1 phase population in parallel with Apoptosis by showing activated Caspase-3, -8 and -9 and PARP induction. These results provide a new strategy for development of novel HSP90 inhibitors for Cancer treatment.

Keywords

Colorectal cancer (CRC); HSP90 inhibitors; Non-small cell lung cancer (NSCLC).

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-146325
    HSP90 Inhibitor
    HSP