Discovery of epigenetic modulators targeting HDACs and EZH2 simultaneously for the treatment of hematological malignancies.

Epigenetic-targeted therapy has been applied in the treatment of several types of cancer. Herein, based on the synergistic antitumor effects of co-targeting HDACs and EZH2 in some hematological malignancies, a novel series of tazemetostat-based HDACs/EZH2 dual inhibitors were rationally designed, synthesized, and biologically evaluated. Satisfyingly, compounds 22a and 22b were identified as potent HDACs/EZH2 dual inhibitors with robust antiproliferative activities against one diffuse large-cell B cell lymphomas (DLBCL) cell line harboring EZH2 mutation and multiple acute myeloid leukemia (AML) cell lines. Notably, after a short-term treatment in the EZH2 mutant DLBCL cell line (SU-DHL-6), 22a and 22b displayed much stronger antiproliferative activities than the approved EZH2 inhibitor tazemetostat, while after a long-term treatment in SU-DHL-6 cells, 22a and 22b displayed comparable or even superior antiproliferative activities to the approved HDACs inhibitor SAHA. In AML cells, compounds 22a and 22b displayed much more potent antiproliferative activities than tazemetostat, as well as distinctive differentiation-inducing abilities and superior apoptosis-inducing abilities relative to tazemetostat and SAHA. Moreover, the synergistic anti-AML effects of HDACs/EZH2 dual inhibitors combined with various anti-AML drugs were demonstrated.