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ACS Comb Sci. 2017 Mar 13;19(3):161-172. doi: 10.1021/acscombsci.6b00174. Epub 2017 Feb 22.

Discovery of Peptidomimetic Ligands of EED as Allosteric Inhibitors of PRC2.

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Center for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill , Chapel Hill, North Carolina 27599, United States.
Structural Genomics Consortium, University of Toronto , Toronto, Ontario M5G 1L7, Canada.
Princess Margaret Cancer Centre and Department of Medical Biophysics, University of Toronto , Toronto, Ontario M5G 2M9, Canada.


The function of EED within polycomb repressive complex 2 (PRC2) is mediated by a complex network of protein-protein interactions. Allosteric activation of PRC2 by binding of methylated proteins to the embryonic ectoderm development (EED) aromatic cage is essential for full catalytic activity, but details of this regulation are not fully understood. EED's recognition of the product of PRC2 activity, histone H3 lysine 27 trimethylation (H3K27me3), stimulates PRC2 methyltransferase activity at adjacent nucleosomes leading to H3K27me3 propagation and, ultimately, gene repression. By coupling combinatorial chemistry and structure-based design, we optimized a low-affinity methylated jumonji, AT-rich interactive domain 2 (Jarid2) peptide to a smaller, more potent peptidomimetic ligand (Kd = 1.14 ± 0.14 μM) of the aromatic cage of EED. Our strategy illustrates the effectiveness of applying combinatorial chemistry to achieve both ligand potency and property optimization. Furthermore, the resulting ligands, UNC5114 and UNC5115, demonstrate that targeted disruption of EED's reader function can lead to allosteric inhibition of PRC2 catalytic activity.


methyllysine; one-bead-one-compound; peptidomimetic; polycomb

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