2. Academic Validation
  3. Repurposing Linezolid in Conjunction with Histone Deacetylase Inhibitor Access in the Realm of Glioblastoma Therapies

Repurposing Linezolid in Conjunction with Histone Deacetylase Inhibitor Access in the Realm of Glioblastoma Therapies

  • J Med Chem. 2025 Jan 21. doi: 10.1021/acs.jmedchem.4c02086.
I-Chung Chen 1,  Hong-Yi Lin 2 3 4,  Zheng-Yang Liu 1,  Wei-Jie Cheng 5,  Tzu-Yi Yeh 1,  Wen-Bin Yang 6 7 8,  Hoang Yen Tran 1 9,  Mei-Jung Lai 5,  Chung-Han Wang 6,  Tzu-Yuan Kao 6,  Chia-Yang Hung 10,  Ya-Lin Huang 1,  Ke-Chi Liou 1,  Chien-Ming Hsieh 1 5 11 12,  Tsung-I Hsu 6 7 8 5 11 13,  Jing-Ping Liou 1 5 11 13
Affiliations

Affiliations

  • 1 School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei 110, Taiwan.
  • 2 Taipei Neuroscience Institute, New Taipei City 235, Taiwan.
  • 3 Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 110, Taiwan.
  • 4 Taiwan Brain Disease Foundation, Taipei 100, Taiwan.
  • 5 TMU Research Center for Drug Discovery, Taipei Medical University, Taipei 110, Taiwan.
  • 6 Ph.D. Program in Medical Neuroscience, College of Medical Science and Technology, Taipei Medical University and National Health Research Institutes, Taipei 110, Taiwan.
  • 7 International Master Program in Medical Neuroscience, College of Medical Science and Technology, Taipei Medical University Taipei 110, Taiwan.
  • 8 TMU Research Center of Neuroscience, Taipei Medical University, Taipei 110, Taiwan.
  • 9 Department of Pharmacology and Clinical Pharmacy, Faculty of Pharmacy, Can Tho University of Medicine and Pharmacy, Can Tho 902342, Vietnam.
  • 10 Department of Immuno-Oncology, Beckman Research Institute, City of Hope, Duarte, California 91010, United States.
  • 11 Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei 110, Taiwan.
  • 12 Department of Pharmaceutics, School of Pharmacy, University College, London WC1N 1AX, U.K.
  • 13 TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei 110, Taiwan.
PMID: 39836457 DOI: 10.1021/acs.jmedchem.4c02086
Abstract

Since decades after temozolomide was approved, no effective drugs have been developed. Undoubtedly, blood-brain barrier (BBB) penetration is a severe issue that should be overcome in glioblastoma multiforme (GBM) drug development. In this research, we were inspired by linezolid through structural modification with several bioactive moieties to achieve the desired brain delivery. The results indicated that the histone deacetylase modification, referred to as compound 1, demonstrated promising cytotoxic effects in various brain tumor cell lines. Further comprehensive mechanism studies indicated that compound 1 induced acetylation, leading to DNA double-strand breaks, and induced the ubiquitination of RAD51, disrupting the DNA repair process. Furthermore, compound 1 also exhibited dramatic improvement in the orthotopic GBM mouse model, demonstrating its efficacy and satisfying BBB penetration. Therefore, the reported compound 1, provided with an independent therapeutic pathway, satisfying elongation in survival and tumor size reduction, and the ability to penetrate the BBB, was potent to achieve further development.

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