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.