Recent advances in EZH2-based dual inhibitors in the treatment of cancers

The enhancer of zeste homolog 2 (EZH2) protein is the catalytic subunit of one of the histone methyltransferases. EZH2 catalyzes the trimethylation of lysine 27 of histone H3 (H3K27me3) and further alters downstream target levels. EZH2 is upregulated in cancer tissues, wherein its levels correlate strongly with cancer genesis, progression, metastasis, and invasion. Consequently, it has emerged as a novel anticancer therapeutic target. Nonetheless, developing EZH2 inhibitors (EZH2i) has encountered numerous difficulties, such as pre-clinical drug resistance and poor therapeutic effect. The EZH2i synergistically suppresses cancers when used in combination with additional antitumor drugs, such as PARP inhibitors, HDAC inhibitors, BRD4 inhibitors, EZH1 inhibitors, and EHMT2 inhibitors. Typically, the use of dual inhibitors of two different targets mediated by one individual molecule has been recognized as the preferred approach for overcoming the limitations of EZH2 monotherapy. The present review discusses the theoretical basis for designing EZH2-based dual-target inhibitors, and also describes some in vitro and in vivo analysis results.