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.
- 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: [email protected].
- 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: [email protected].
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.