2. Academic Validation
  3. Pragmatic recruitment of memantine as the capping group for the design of HDAC inhibitors: A preliminary attempt to unravel the enigma of glioblastoma

Pragmatic recruitment of memantine as the capping group for the design of HDAC inhibitors: A preliminary attempt to unravel the enigma of glioblastoma

  • Eur J Med Chem. 2021 May 5:217:113338. doi: 10.1016/j.ejmech.2021.113338.
Kunal Nepali 1,  Tsung-I Hsu 2,  Chien-Ming Hsieh 1,  Wei-Lun Lo 3,  Mei-Jung Lai 4,  Kai-Cheng Hsu 5,  Tony Eight Lin 6,  Jian-Ying Chuang 7,  Jing-Ping Liou 8
Affiliations

Affiliations

  • 1 School of Pharmacy, College of Pharmacy, Taipei Medical University, 250 Wuxing Street, Taipei, 11031, Taiwan.
  • 2 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.
  • 3 Division of Neurosurgery, Taipei Medical University-Shuang-Ho Hospital, Taiwan.
  • 4 Biomedical Commercialization Center, Taipei Medical University, Taipei, 11031, Taiwan.
  • 5 Biomedical Commercialization Center, Taipei Medical University, Taipei, 11031, Taiwan; Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taiwan; Graduate Institute of Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taiwan.
  • 6 Graduate Institute of Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taiwan.
  • 7 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: chuangcy@tmu.edu.tw.
  • 8 School of Pharmacy, College of Pharmacy, Taipei Medical University, 250 Wuxing Street, Taipei, 11031, Taiwan; Biomedical Commercialization Center, Taipei Medical University, Taipei, 11031, Taiwan. Electronic address: jpl@tmu.edu.tw.
PMID: 33744690 DOI: 10.1016/j.ejmech.2021.113338
Abstract

Hurdled and marred by the notorious nature of glioblastomas (GBM) in terms of resistance to therapy and limited drug delivery into the brain, the anti-GBM drug pipeline is required to be loaded with mechanistically diverse agents. The consideration of HDAC inhibition as a prudent approach to circumvent the resistance issue in GBM spurred us to pragmatically design and synthesizes hydroxamic acids endowed with CNS penetrating ability. By virtue of the blood brain barrier permeability (BBB), memantine was envisioned as an appropriate CAP component for the construction of the HDAC inhibitors. Diverse linkers were stapled for the tetheration of the zinc binding motif with the CAP group to pinpoint an appropriate combination (CAP and linker) that could confer inhibitory preference to HDAC6 isoform (overexpressed in GBM). Resultantly, hydroxamic acid 16 was identified as a promising compound that elicited striking antiproliferative effects against Human U87MG GBM cells as well as TMZ-resistant GBM cells and P1S cells, a concurrent chemo radiotherapy (CCRT)-resistant/patient-derived glioma cell line mediated through preferential HDAC6 inhibition (IC50 = 5.42 nM). Furthermore, 16 exerted cell cycle arrest at G2 phase, induced Apoptosis in GBM cells at high concentration and exhibited high BBB permeability. To add on, in-vivo study revealed that the administration of compound 16 prolonged the survival of TMZ-resistant U87MG inoculated orthotopic mice. Overall, the cumulative results indicate that 16 is a tractable CNS penetrant preferential HDAC6 Inhibitor that might emerge as a potent weapon against GBM.

Keywords

Glioblastoma; HDAC6; Hydroxamic acid; Linker; Memantine; Resistant.

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