Sharad K. Verma

TL;DR: GSK126, a potent, highly selective, S-adenosyl-methionine-competitive, small-molecule inhibitor of EZH2 methyltransferase activity, decreases global H3K27me3 levels and reactivates silenced PRC2 target genes and markedly inhibits the growth of EzH2 mutant DLBCL xenografts in mice are demonstrated.

TL;DR: GC B cell (GCB)-type diffuse large B cell lymphomas (DLBCLs) are mostly addicted to EZH2 but not the more differentiated activated B cell(ABC)-type DLBCLS, thus clarifying the therapeutic scope of EZh2 targeting.

TL;DR: It is concluded that epigenetic modifiers are the first rational therapeutic candidates for this deadly malignancy, which is epigenetically deregulated but genetically bland.

TL;DR: This work has identified highly potent, selective, SAM-competitive, and cell-active EZH2 inhibitors, including GSK926 and GSK343, which are small molecule chemical tools that would be useful to further explore the biology of EZh2.

TL;DR: The data suggest that activation of EZH2 allows the enzyme to adopt a conformation that possesses greater affinity for GSK126, and the long residence time of GSK 126 may be beneficial in vivo and may result in durable target inhibition after drug systemic clearance.