Design, Synthesis, and Biological Evaluation of Potent EZH2/LSD1 Dual Inhibitors for Prostate Cancer

As histone modification enzymes, EZH2 mediates H3K27
trimethylation
(H3K27me3), whereas LSD1 removes methyl groups from H3K4me1/2 and
H3K9me1/2. Synergistic anticancer effects of combining inhibitors
of these two enzymes are observed in leukemia and prostate cancer.
Thus, a series of EZH2/LSD1 dual inhibitors are designed and synthesized
to evaluate their anticancer activity. After the structure–activity
study, one of the best compounds, ML234, displayed excellent
antiproliferative capacity against prostate cancer cell lines LNCAP,
PC3, and 22RV1. Enzymatic assays ascertained that the anticancer potency
of ML234 was mediated through coinhibition of EZH2 and
LSD1. Moreover, the accumulation of H3K4me2 and H3K9me2 and the decrease
of H3K27me3 induced by ML234 were verified by Western
blot analysis. More importantly, the compound remarkably suppressed
the tumor growth and enhanced the therapeutic efficacy of clinical
drug enzalutamide in the 22RV1 xenograft mouse model, indicating that
it may have potential as an anticancer agent in prostate cancer.