pocket of DNA methyltransferases to block methyl transfer. EI1 is another inhibitor, developed by Novartis, that showed EZH2 inhibitory activity in lymphoma tumor cells, including cells with the Y641 mutation. The mechanism of this inhibitor also involves competing with the SAM cofactor for binding to EZH2. GSK126 GSK126 is a potent, SAM-competitive EZH2 inhibitor developed by GlaxoSmithKline, that has 150-fold selectivity over EZH1 and a Ki of 0.5-3 nM. UNC1999 was developed as an analogue of GSK126, and was the first orally bioavailable EZH2 inhibitor to show activity. However, it is less selective than its counterpart GSK126, and it binds to EZH1 as well, increasing the potential for off-target effects. Combination therapies are being studied as possible treatments when primary treatments begin to fail. Etoposide, a topoisomerase inhibitor, when combined with an EZH2 inhibitor, becomes more effective for non-small cell lung cancers with BRG1 and EGFR mutations. However, EZH2 and lysine methylation can have tumor suppressing activity, for example in myelodysplastic syndrome, indicating that EZH2 inhibition may not be beneficial in all cases. Weaver Syndrome Mutations in the EZH2 gene have been linked with Weaver syndrome, a rare disorder characterized by advanced bone age, macrocephaly, and hypertelorism. The histidine residue in the active site of the wild-type EZH2 was mutated to tyrosine in patients diagnosed with Weaver syndrome. The mutation likely interferes with cofactor binding and causes disruption of the natural function of the protein. Taxonomic distribution Enhancer of zeste (E(z)) was originally identified in Drosophila melanogaster, and its mammalian homologs were subsequently identified and named EZH1 (enhancer of zeste homolog 1) and EZH2 (enhancer of zeste homolog 2). EZH2 is highly conserved through evolution. It and its homologs play essential roles in development, cell differentiation, and cell division in plants, insects, fish, and mammals. The following taxonomic tree is a depiction of EZH2's distribution throughout a wide variety of species. See also Ezh2 gene References Further reading EC 2.1.1