Discovery of Peptidomimetic Ligands of EED as Allosteric Inhibitors of PRC2

Barnash, Kimberly D.; The, Juliana; Norris-Drouin, Jacqueline L.; Cholensky, Stephanie H.; Worley, Beau M.; Li, Fengling; Stuckey, Jacob I.; Brown, Peter J.; Vedadi, Masoud; Arrowsmith, Cheryl H.; Frye, Stephen V.; James, Lindsey I.

doi:10.1021/acscombsci.6b00174

Title: Discovery of Peptidomimetic Ligands of EED as Allosteric Inhibitors of PRC2

Journal Article · Wed Feb 22 00:00:00 EST 2017 · ACS Combinatorial Science

DOI:https://doi.org/10.1021/acscombsci.6b00174· OSTI ID:1351384

Barnash, Kimberly D. ^[1]; The, Juliana ^[2]; Norris-Drouin, Jacqueline L. ^[1]; Cholensky, Stephanie H. ^[1]; Worley, Beau M. ^[1]; Li, Fengling ^[2]; Stuckey, Jacob I. ^[1]; Brown, Peter J. ^[2]; Vedadi, Masoud ^[2]; Arrowsmith, Cheryl H. ^[2]; Frye, Stephen V. ^[1];

^[1]

Univ. of North Carolina, Chapel Hill, NC (United States)
Univ. of Toronto, ON (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 (K_d = 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.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES)

Grant/Contract Number:: R01GM100919

OSTI ID:: 1351384

Journal Information:: ACS Combinatorial Science, Vol. 19, Issue 3; ISSN 2156-8952

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Cited by: 35 works

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Figures / Tables (9)

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Table 1 ; Part 1(p. 16)

Table 1: Part 2(p. 17)

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Related Subjects

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY
60 APPLIED LIFE SCIENCES
Peptides and proteins
Ligands
Monomers
Catalytic activity
Aromatic compounds