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

I. Chung Chen, Hong Yi Lin, Zheng Yang Liu, Wei Jie Cheng, Tzu Yi Yeh, Wen Bin Yang, Hoang Yen Tran, Mei Jung Lai, Chung Han Wang, Tzu Yuan Kao, Chia Yang Hung, Ya Lin Huang, Ke Chi Liou, Chien Ming Hsieh, Tsung I. Hsu, Jing Ping Liou

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)2779-2803
Number of pages25
JournalJournal of Medicinal Chemistry
Volume68
Issue number3
DOIs
Publication statusPublished - 2025

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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