Design, Synthesis, and Biological Evaluation of a Potent Dual EZH2–BRD4 Inhibitor for the Treatment of Some Solid Tumors

Enhancer of zeste homolog 2 (EZH2) mediates the trimethylation
of histone 3 lysine 27 (H3K27) to promote gene silencing. Inhibition
of EZH2 is a viable strategy for cancer treatment; however, only a
small subset of hematological malignancies are sensitive to small-molecule
EZH2 inhibitors. EZH2 inhibitors cause H3K27 acetylation in most solid
tumors, leading to drug resistance. Bromodomain-containing protein
4 (BRD4) inhibitors were reported to enhance the sensitivity of solid
tumors to EZH2 inhibitors. Thus, we designed and evaluated a series
of dual EZH2–BRD4 inhibitors. ZLD-2, the most promising compound,
exhibited potent inhibitory activity against EZH2 and BRD4. Compared
to the EZH2 inhibitor GSK126, ZLD-2 displayed potent antiproliferation
activity against breast, lung, bladder, and pancreatic cancer cells.
In vivo, ZLD-2 exhibited antitumor activity in a BxPC-3 mouse xenograft
model, whereas GSK126 promoted tumor growth. Thus, ZLD-2 may be a
lead compound for treating solid tumors.