Histone Deacetylase and Enhancer of Zeste Homologue 2 Dual Inhibitors Presenting a Synergistic Effect for the Treatment of Hematological Malignancies

Aberrance of epigenetic modification is one of the important
factors
leading to hematological malignancies. Histone deacetylase (HDAC)
inhibitors and enhancers of zeste homologue 2 (EZH2) inhibitors are
demonstrated to be significant epigenic modulators. Cocktail therapy
of HDAC inhibitors and EZH2 inhibitors was demonstrated to be a promising
strategy in hematological malignancies. We designed HDAC and EZH2
dual inhibitors based on the strong synergistic effect of SAHA and
GSK126. Compound 20 exhibited excellent inhibitory activity
against HDAC1 (IC50 = 0.12 μM) and EZH2 (IC50 = 0.059 μM), it also showed good antiproliferation activity
against MV4-11 (IC50 = 0.17 μM), which has more potential
than the cocktail therapy of SAHA and GSK126 (IC50 = 0.40
μM). 20 suppressed tumor growth in vivo, which
was as good as the combination therapy. These results suggested that 20 may be a promising drug candidate for treating hematological
malignancies.