2. Academic Validation
  3. Design, synthesis, and biological activity of dual monoamine oxidase A and heat shock protein 90 inhibitors, N-Methylpropargylamine-conjugated 4-isopropylresorcinol for glioblastoma

Design, synthesis, and biological activity of dual monoamine oxidase A and heat shock protein 90 inhibitors, N-Methylpropargylamine-conjugated 4-isopropylresorcinol for glioblastoma

  • Eur J Med Chem. 2023 Aug 5;256:115459. doi: 10.1016/j.ejmech.2023.115459.
Hui-Ju Tseng 1,  Suddhasatwa Banerjee 2,  Bin Qian 3,  Mei-Jung Lai 4,  Tung-Yun Wu 5,  Tsung-I Hsu 6,  Tony Eight Lin 7,  Kai-Cheng Hsu 7,  Kuo-Hsiang Chuang 8,  Jing-Ping Liou 9,  Jean C Shih 10
Affiliations

Affiliations

  • 1 Department of Pharmacology and Pharmaceutical Sciences, Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences, University of Southern California, Los Angeles, CA, 90089, United States; School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, 110031, Taiwan.
  • 2 School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, 110031, Taiwan.
  • 3 Department of Pharmacology and Pharmaceutical Sciences, Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences, University of Southern California, Los Angeles, CA, 90089, United States.
  • 4 TMU Research Center for Drug Discovery, Taipei Medical University, Taipei, 110031, Taiwan.
  • 5 Ph.D. Program in Clinical Drug Development of Herbal Medicine, College of Pharmacy, Taipei Medical University, Taipei, 110031, Taiwan.
  • 6 Ph.D. Program in Medical Neuroscience, College of Medical Science and Technology, Taipei Medical University and National Health Research Institutes, Taipei, 11031, Taiwan; International Master Program in Medical Neuroscience, College of Medical Science and Technology, Taipei Medical University, Taipei, 11031, Taiwan.
  • 7 Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, 11031, Taiwan; Ph.D. Program in Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, 11031, Taiwan.
  • 8 TMU Research Center for Drug Discovery, Taipei Medical University, Taipei, 110031, Taiwan; Graduate Institute of Pharmacognosy, College of Pharmacy, Taipei Medical University, Taipei, 110031, Taiwan.
  • 9 School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, 110031, Taiwan; TMU Research Center for Drug Discovery, Taipei Medical University, Taipei, 110031, Taiwan; Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei, 11031, Taiwan. Electronic address: jpl@tmu.edu.tw.
  • 10 Department of Pharmacology and Pharmaceutical Sciences, Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences, University of Southern California, Los Angeles, CA, 90089, United States; Department of Integrative Anatomical Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, United States; Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, United States; USC-Taiwan Center for Translational Research, Los Angeles, CA, 90089, United States. Electronic address: jcshih@usc.edu.
PMID: 37172473 DOI: 10.1016/j.ejmech.2023.115459
Abstract

Monoamine Oxidase A (MAO A) and heat shock protein 90 (HSP90) inhibitors have been shown to decrease the progression of glioblastoma (GBM) and Other cancers. In this study, a series of MAO A/HSP90 dual inhibitors were designed and synthesized in the hope to develop more effective treatment of GBM. Compounds 4-b and 4-c are conjugates of isopropylresorcinol (pharmacophore of HSP90 Inhibitor) with the phenyl group of clorgyline (MAO A inhibitor) by a tertiary amide bond substituted with methyl (4-b) or ethyl (4-c) group, respectively. They inhibited MAO A activity, HSP90 binding, and the growth of both TMZ-sensitive and -resistant GBM cells. Western blots showed that they increased HSP70 expression indicating reduced function of HSP90, reduced HER2 and phospho-Akt expression similar to MAO A or HSP90 Inhibitor itself. Both compounds decreased IFN-γ induced PD-L1 expression in GL26 cells, suggesting they can act as Immune Checkpoint Inhibitor. Further, they reduced tumor growth in GL26 mouse model. NCI-60 analysis showed they also inhibited the growth of colon Cancer, leukemia, non-small cell lung and Other cancers. Taken together, this study demonstrates MAO A/HSP90 dual inhibitors 4-b and 4-c reduced the growth of GBM and Other cancers, and they have potential to inhibit tumor immune escape.

Keywords

Glioblastoma; Heat shock protein 90; Monoamine oxidase A; PD-L1 expression.

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