molecules of the month

Context. MAK683 is an oral, allosteric and selective PRC2 inhibitor intended for PRC2-dependent cancers. PRC2 is an essential epigenetic regulator of gene expression and enhanced or diminished PRC2 function have been implicated in a number of cancers. Enhancer of zeste homolog 2 (EZH2), one of the four core components of PRC2 that directly trimethylates K27 of histone 3 (H3K27me3), has been the most extensively studied PRC2 subunit and a number of EZH2 mutations and post-translational modifications have reportedly been associated with disease progression. In addition, the approval of the first EZH2 inhibitor, Epizyme’s tazemetostat, for advanced/metastatic epithelioid sarcoma and relapsed/refractory follicular lymphoma further validated EZH2 and other PRC2 components as viable drug targets. Resistance mechanisms to EZH2 inhibitors have been…