Design and Synthesis of Dual EZH2/BRD4 Inhibitors to Target Solid Tumors

EZH2 inhibitors that prevent trimethylation
of histone lysine 27
(H3K27) are often limited to the treatment of a subset of hematological
malignancies. In most solid tumors, EZH2 inhibitors induce reciprocal
H3K27 acetylation that subsequently results in acquired drug resistance.
The combination of EZH2 and BRD4 inhibitors to resensitize solid cancer
cells to EZH2 inhibitors has proven to be effective, underlying the
significance of developing dual inhibitors. Herein, we present the
design, synthesis, and biological evaluation of first-in-class dual
EZH2/BRD4 inhibitors. Our most promising compound, YM458, displays
potent inhibitory activity against EZH2 and BRD4 and remarkable antiproliferative
capacity against 11 solid cancer cell lines. Its in vivo therapeutic
potential is validated in both lung cancer and pancreatic cancer xenograft
tumor mice models, highlighting the potential of EZH2/BRD4 dual inhibitors
to target a broad scope of EZH2 inhibitor-resistant solid tumors.