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EZH2 (enhancer of zeste homolog 2) is the catalytic subunit of the protein lysine methyltransferase (PKMT) polycomb repressive complex 2 (PRC2), a multi-protein complex that uniquely catalyzes the mono-, di- and tri-methylation of histone H3 lysine 27 (H3K27). Hyper-tri-methylation of H3K27, by various mechanisms, has been identified as a driver of tumorigenesis for multiple human cancers. In particular, gain-of-function mutations in EZH2 result in elevated H3K27me3 in germinal center non-Hodgkin’s lymphomas and a synthetic lethal relationship with loss-of-function mutations of the opposing chromatin modifier SWI/SNF, results in an essential dependency on EZH2 activity among several soft tissue sarcomas, such as malignant rhabdoid tumor and epithelioid sarcoma (ES). In this chapter, we describe the discovery and clinical development of tazemetostat, a potent and selective EHZ2 inhibitor that represents the first PKMT inhibitor to be approved for use in treating human cancers, specifically ES and follicular lymphoma (FL).

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