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

EZH2 inhibitors that prevent trimethylation ofhistone lysine 27 (H3K27) are often limited to the treatment of asubset of hematological malignancies. In most solid tumors, EZH2inhibitors induce reciprocal H3K27 acetylation that subsequentlyresults in acquired drug resistance. The combination of EZH2 andBRD4 inhibitors to resensitize solid cancer cells to EZH2inhibitors has proven to be effective, underlying the significanceof developing dual inhibitors. Herein, we present the design,synthesis, and biological evaluation offirst-in-class dual EZH2/BRD4 inhibitors. Our most promising compound, YM458, displayspotent inhibitory activity against EZH2 and BRD4 and remarkableantiproliferative capacity against 11 solid cancer cell lines. Its in vivo therapeutic potential is validated in both lung cancer andpancreatic cancer xenograft tumor mice models, highlighting the potential of EZH2/BRD4 dual inhibitors to target a broad scope ofEZH2 inhibitor-resistant solid tumors

Automated summary

This study presents the design, synthesis, and biological evaluation of first-in-class dual EZH2/BRD4 inhibitors. The most promising compound, YM458, demonstrates potent inhibitory activity against EZH2 and BRD4 and remarkable antiproliferative capacity against various solid cancer cell lines. In vivo experiments validate the therapeutic potential of EZH2/BRD4 dual inhibitors in lung cancer and pancreatic cancer xenograft tumor models, highlighting their potential to target a broad scope of resistant solid tumors.