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

Sachin Sharma, Shao An Wang, Wen Bin Yang, Hong Yi Lin, Mei Jung Lai, Hsien Chung Chen, Tzu Yuan Kao, Feng Lin Hsu, Kunal Nepali, Tsung I. Hsu, Jing Ping Liou

研究成果: 雜誌貢獻文章同行評審

摘要

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.
原文英語
頁(從 - 到)2963-2985
頁數23
期刊Journal of Medicinal Chemistry
67
發行號4
DOIs
出版狀態已發佈 - 2月 22 2024

ASJC Scopus subject areas

  • 分子醫學
  • 藥物發現

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