Abstract
Abstract Enhance of Zeste Homolog 2 (EZH2) is the biochemical activity of the Polycomb Repressive Complex 2 (PRC2) that transfers a methyl group from the cofactor S-adenosyl methionine (SAM) to histone H3 on lysine 27 (H3K27), resulting in epigenetic silencing of target gene expression. Activity of the multi-component PRC2 complex is crucial for normal development and differentiation. However, dysregulation of H3K27 methylation is implicated in tumorigenesis and occurs through multiple mechanisms. Elevated levels of EZH2 correlate with poor prognosis in a number of solid tumors including prostate, breast, kidney and lung. The increased EZH2 expression observed in many solid tumors has been linked to loss of one or more miRNAs including mir-101, mir-26A, and mir-214; aberrant E2F activity and chromosomal amplification. Inactivating mutations in UTX, an H3K27 demethylase which acts in opposition to EZH2, have been described in several tumor types including transitional cell bladder carcinoma, esophageal squamous cell carcinoma, renal cell carcinoma and multiple myeloma. Recently, somatic activating mutations in EZH2 have been identified in follicular lymphoma (FL) and GCB diffuse large B cell lymphoma (DLBCL). The frequency of the most prevalent mutation, Y641, is reported to be 7-12% in FL and as high as 22% in DLBCL. In view of the above, biochemical inhibitors of EZH2 may have therapeutic utility and herein we report on the identification and characterization of potent and selective small molecule EZH2 inhibitors with in vitro and in vivo antiproliferative activity in cancer cell lines and mouse xenografts. The studies provide a compelling rationale for the clinical evaluation of EZH2 inhibitors in EZH2 driven human cancers. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr SY02-02. doi:1538-7445.AM2012-SY02-02
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