2. Academic Validation
  3. Rationally designed donepezil-based hydroxamates modulate Sig-1R and HDAC isoforms to exert anti-glioblastoma effects

Rationally designed donepezil-based hydroxamates modulate Sig-1R and HDAC isoforms to exert anti-glioblastoma effects

  • Eur J Med Chem. 2023 Feb 15:248:115054. doi: 10.1016/j.ejmech.2022.115054.
Kunal Nepali 1,  An-Chih Wu 2,  Wei-Lun Lo 3,  Bhawna Chopra 4,  Mei-Jung Lai 5,  Jian-Ying Chuang 6,  Jing-Ping Liou 7
Affiliations

Affiliations

  • 1 School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan; TMU Research Center for Drug Discovery, Taipei Medical University, Taipei, Taiwan.
  • 2 Department of Neurosurgery, Keelung Chang Gung Memorial Hospital, Chang Gung University, Taiwan.
  • 3 Division of Neurosurgery, Shuang Ho Hospital, Taipei Medical University, Taiwan; Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University Taipei Neuroscience Institute, Taiwan.
  • 4 Department of Pharmaceutical Sciences, Guru Gobind Singh College of Pharmacy, Near Guru Nanak Khalsa College, Yamuna Nagar, 135001, Haryana, India.
  • 5 TMU Research Center for Drug Discovery, Taipei Medical University, Taipei, Taiwan.
  • 6 TMU Research Center for Drug Discovery, Taipei Medical University, Taipei, Taiwan; The Ph.D. Program for Neural Regenerative Medicine, College of Medical Science and Technology, Taipei Medical University, Taiwan; TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taiwan; Cell Physiology and Molecular Image Research Center, Wan Fang Hospital, Taipei Medical University, Taiwan. Electronic address: [email protected].
  • 7 School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan; TMU Research Center for Drug Discovery, Taipei Medical University, Taipei, Taiwan. Electronic address: [email protected].
PMID: 36630883 DOI: 10.1016/j.ejmech.2022.115054
Abstract

The pursuit of activating the HDAC inhibitory template towards additional mechanisms spurred us to design dual modulators (Sig-1R agonist - HDAC Inhibitor) via utilization of the core structural unit of donepezil (an FDA-approved anti-Alzheimer's agent) as a surface recognition part. Literature precedents coupled with our experience rendered us with several insights that led to the inclusion of chemically diverse linkers and hydroxamic acid (zinc-binding motif) as the Other components of HDAC inhibitory pharmacophore. With this envisionment and clarity, donepezil-based HDAC inhibitory adducts were furnished and exhaustively explored for their anti-GBM efficacy. Resultantly, a magnificently potent HDAC Inhibitor 10 [IC50 (HDAC6) = 2.7 nM, IC50 (HDAC2) = 0.71 μM] was pinpointed that was endowed with the ability to: i) exert cell growth inhibitory effects against Human U87MG GBM cells ii) cause death in TMZ-resistant GBM cells iii) induce subG1 arrest in GBM cells iv) prolong the survival of TMZ-resistant U87MG inoculated orthotopic mice (in-vivo studies) v) induce GBM cell Apoptosis via binding to Sig-1R. Collectively, the results led to the identification of compound 10 as a tractable anti-GBM agent that deserves detailed investigation for the accomplishment of its candidature as a GBM therapeutic.

Keywords

Donepezil; GBM cells; HDAC inhibitor; HDAC2; HDAC6; Sigma-1 agonist; TMZ resistant.

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