decitabine + tazemetostat

decitabine + tazemetostat is an experimental epigenetic combination regimen that pairs the DNA hypomethylating agent decitabine, a nucleoside analog DNA methyltransferase (DNMT) inhibitor, with tazemetostat, a selective small-molecule inhibitor of the histone methyltransferase enhancer of zeste homolog 2 (EZH2). Decitabine incorporates into DNA and forms covalent adducts with DNMT1, leading to its degradation and global DNA hypomethylation, while tazemetostat blocks EZH2-mediated trimethylation of histone H3 on lysine 27 (H3K27me3), reactivating silenced tumor suppressor and immune-related genes. Preclinical work in T-cell leukemias and other malignancies has shown that combining DNA demethylating agents such as decitabine with EZH2 inhibitors such as tazemetostat can synergistically suppress tumor growth by dual targeting of aberrant DNA and histone methylation, restoring expression of negative regulators of MAPK signaling and cell-cycle control and enhancing immune susceptibility of tumor cells.[1][6]