First-in-Class Dual EZH2-HSP90 Inhibitor Eliciting Striking Antiglioblastoma Activity In Vitro and In Vivo .
Sachin SharmaShao-An WangWen-Bin YangHong-Yi LinMei-Jung LaiHsien-Chung ChenTzu-Yuan KaoFeng-Lin HsuKunal NepaliTsung-I HsuJing Ping LiouPublished in: Journal of medicinal chemistry (2024)
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.
Keyphrases
- cell cycle arrest
- cell death
- gene expression
- pi k akt
- induced apoptosis
- heat shock protein
- reactive oxygen species
- heat shock
- phase iii
- heat stress
- dna methylation
- long non coding rna
- signaling pathway
- endoplasmic reticulum stress
- long noncoding rna
- oxidative stress
- randomized controlled trial
- drug induced
- metabolic syndrome
- cell proliferation
- quantum dots
- endothelial cells
- risk assessment
- human health
- phase ii
- high glucose
- high fat diet induced
- double blind
- light emitting