First-in-Class Dual EZH2-HSP90 Inhibitor Eliciting Striking Antiglioblastoma Activity In Vitro and In Vivo

  • J Med Chem. 2024 Feb 22;67(4):2963-2985. doi: 10.1021/acs.jmedchem.3c02053.
Sachin Sharma  1 ,  Shao-An Wang  2 ,  Wen-Bin Yang  3 ,  Hong-Yi Lin  4 ,  Mei-Jung Lai  5 ,  Hsien-Chung Chen  3  6  7 ,  Tzu-Yuan Kao  1  7 ,  Feng-Lin Hsu  2 ,  Kunal Nepali  1  5  8 ,  Tsung-I Hsu  3  5  7  9  10 ,  Jing-Ping Liou  1  5  10  8
Affiliations
  • 1. School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei 110, Taiwan.
  • 2. School of Respiratory Therapy, College of Medicine, Taipei Medical University, Taipei 110, Taiwan.
  • 3. TMU Research Center of Neuroscience, Taipei Medical University, Taipei 110, Taiwan.
  • 4. Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 110, Taiwan.
  • 5. TMU Research Center for Drug Discovery, Taipei Medical University, Taipei 110, Taiwan.
  • 6. Department of Neurosurgery, Shuang Ho Hospital, Taipei Medical University, Taipei 110, Taiwan.
  • 7. Ph.D. Program in Medical Neuroscience, College of Medical Science and Technology, Taipei Medical University and National Health Research Institutes, Taipei 110, Taiwan.
  • 8. Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei 110, Taiwan.
  • 9. International Master Program in Medical Neuroscience, College of Medical Science and Technology, Taipei Medical University, Taipei 110, Taiwan.
  • 10. TMU Research Center of Cancer Translational Medicine, Taipei 110 Taiwan.
PMID: 38285511 DOI: 10.1021/acs.jmedchem.3c02053
Abstract

Structural analysis of tazemetostat, an FDA-approved EZH2 Inhibitor, led us to pinpoint a suitable site for appendage with a pharmacophoric fragment of second-generation HSP90 inhibitors. Resultantly, a magnificent dual EZH2/HSP90 Inhibitor was pinpointed that exerted striking cell growth inhibitory efficacy against TMZ-resistant Glioblastoma (GBM) cell lines. Exhaustive explorations of chemical probe 7 led to several revelations such as (i) compound 7 increased Apoptosis/necrosis-related gene expression, whereas decreased M phase/kinetochore/spindle-related gene expression as well as CENPs protein expression in Pt3R cells; (ii) dual inhibitor 7 induced cell cycle arrest at the M phase; (iii) compound 7 suppressed Reactive Oxygen Species (ROS) catabolism pathway, causing the death of TMZ-resistant GBM cells; and (iv) compound 7 elicited substantial in vivo anti-GBM efficacy in experimental mice xenografted with TMZ-resistant Pt3R cells. Collectively, the study results confirm the potential of dual EZH2-HSP90 inhibitor 7 as a tractable anti-GBM agent.

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