Chemical Probes Targeting Polycomb Repressive Complex 2 Gene Repression

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DESCRIPTION (provided by applicant): Polycomb group proteins (PcG) are transcriptional repressors that bind the promoters of genes encoding proteins with key roles in cell fate determination in many cellular lineages. These proteins mediate their functions by silencing inappropriate expressions and maintaining a chromatin repressive state. PcG proteins are known to form large multimeric complexes of two general types, PRC1 and PRC2. PRC2 is involved in the initiation of gene repression and it has intrinsic histone methyltransferase activiy, with specificity for lysine 27 of histone H3 (H3K27), whereas PRC1 is important for effecting transcriptional repression. A large body of literature links PRC2 components EZH2, EED and SUZ12 to tumor genesis, poor prognosis and tumor proliferation. Overexpression of these proteins leads to enzymatic hyperactivity of the complex, which translates into aberrant repression of tumor suppressor genes in diverse cancers. Thus, targeting the inactivation of the PRC2 complex with chemical probes has emerged as a high-priority strategy to develop novel epigenetic cancer therapies. This idea has been supported by prior studies in which knockdown or knockout of EZH2 or EED impaired proliferation of MLL-AF9 cells, and by recent reports showing the utility of disabling PRC2 complex activity for the treatment of PCR2-dependent human cancers. Despite the importance of PcG proteins in cancer biology, the function of individual PcG members is still poorly understood. We are only beginning to understand now how the PcG proteins actually regulate their target genes. Discovering novel research tools useful to elucidate the specific role of these basic epigenetic regulators in neoplastic development is, therefore, an area of great interest. This proposal attempts to address this need by developing, for the first time, potent and proteolytically stable peptidomimetic and small-molecule inhibitors of the PcG proteins EED and SUZ12, two key components of the PRC2 complex. We have hypothesized that selective inhibition of the EED or SUZ12/repressive trimethyl-lysine association will abolish the PRC2 catalytic activity, and consequently, its biological functions. Hence, these chemical ligands could be useful not only to study the particular role of this protein in different cellular processes but also to decipher the role of PR2 target genes in cancer biology.