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Epizyme Publishes Data Suggesting Compound Activity against Lymphoma with EZH2 Mutations

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Researchers from Epizyme and elsewhere have reported that the company's investigational compound EPZ5687 targets and destroys lymphoma cells harboring mutations in EZH2, a type of histone-modifying enzyme.

EZH2 is involved in the triple-methylation of histone protein H3 lysine 27, or H3K27. Point mutations such as Tyr641 and Ala677 in EZH2 occur in some patients with non-Hodgkin's lymphoma and cause H3K27 to hypermethylate. In a study published in Nature Chemical Biology on Sept. 30, researchers led by Epizyme's Sarah Knutson reported that EPZ5687 reduced methylation in lymphoma cells, which in turn kills Tyr641 and Ala677 mutant cells and has limited effect on wild-type cells.

EPZ5687 is an EZH2 inhibitor proprietary to Epizyme. Study investigators screened 175,000 compounds to identify EPZ5687 and characterize its potency. Then, they tested the compound's ability to inhibit methylation of H3K27 in lymphoma cells and characterized its ability to hinder cell growth in wild-type and mutant lymphoma cell lines.

EPZ5687 "has greater than 500-fold selectivity against 15 other protein methyltransferases and has 50-fold selectivity against the closely related enzyme EZH1," Knutson et al. reported.

Additionally, data from the study "suggest that genetic alteration of EZH2 (for example, mutations at Tyr641 or Ala677) results in a critical dependency on enzymatic activity for proliferation (that is, the equivalent of oncogene addiction), thus portending the clinical use of EZH2 inhibitors for cancers in which EZH2 is genetically altered," the study authors wrote.

In the paper, the authors note that this data is preliminary and requires further in vitro investigations. The researchers do not yet recommend lymphoma patients harboring these mutations be treated with EZH2 inhibitors based on these preliminary findings.

Epizyme is developing personalized drugs that inhibit histone methyltransferase enzymes associated with specific genetic alterations. In addition to EZH2 inhibitors, Epizyme is developing drugs that target DOT1L, an oncogenic driver gene, found in so-called mixed lineage leukemias, characterized by a chromosomal translocation involving chromosome 11. This translocation results in the formation of a fusion of the MLL protein with a variety of partner molecules, according to Epizyme (PGx Reporter 5/16/2012).

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