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Title: SAR of amino pyrrolidines as potent and novel protein-protein interaction inhibitors of the PRC2 complex through EED binding

Authors:
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Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
INDUSTRY
OSTI Identifier:
1357624
Resource Type:
Journal Article
Resource Relation:
Journal Name: Bioorganic and Medicinal Chemistry Letters; Journal Volume: 27; Journal Issue: 7
Country of Publication:
United States
Language:
ENGLISH

Citation Formats

Curtin, Michael L., Pliushchev, Marina A., Li, Huan-Qiu, Torrent, Maricel, Dietrich, Justin D., Jakob, Clarissa G., Zhu, Haizhong, Zhao, Hongyu, Wang, Ying, Ji, Zhiqin, Clark, Richard F., Sarris, Kathy A., Selvaraju, Sujatha, Shaw, Bailin, Algire, Mikkel A., He, Yupeng, Richardson, Paul L., Sweis, Ramzi F., Sun, Chaohong, Chiang, Gary G., and Michaelides, Michael R. SAR of amino pyrrolidines as potent and novel protein-protein interaction inhibitors of the PRC2 complex through EED binding. United States: N. p., 2017. Web. doi:10.1016/j.bmcl.2017.02.030.
Curtin, Michael L., Pliushchev, Marina A., Li, Huan-Qiu, Torrent, Maricel, Dietrich, Justin D., Jakob, Clarissa G., Zhu, Haizhong, Zhao, Hongyu, Wang, Ying, Ji, Zhiqin, Clark, Richard F., Sarris, Kathy A., Selvaraju, Sujatha, Shaw, Bailin, Algire, Mikkel A., He, Yupeng, Richardson, Paul L., Sweis, Ramzi F., Sun, Chaohong, Chiang, Gary G., & Michaelides, Michael R. SAR of amino pyrrolidines as potent and novel protein-protein interaction inhibitors of the PRC2 complex through EED binding. United States. doi:10.1016/j.bmcl.2017.02.030.
Curtin, Michael L., Pliushchev, Marina A., Li, Huan-Qiu, Torrent, Maricel, Dietrich, Justin D., Jakob, Clarissa G., Zhu, Haizhong, Zhao, Hongyu, Wang, Ying, Ji, Zhiqin, Clark, Richard F., Sarris, Kathy A., Selvaraju, Sujatha, Shaw, Bailin, Algire, Mikkel A., He, Yupeng, Richardson, Paul L., Sweis, Ramzi F., Sun, Chaohong, Chiang, Gary G., and Michaelides, Michael R. Sat . "SAR of amino pyrrolidines as potent and novel protein-protein interaction inhibitors of the PRC2 complex through EED binding". United States. doi:10.1016/j.bmcl.2017.02.030.
@article{osti_1357624,
title = {SAR of amino pyrrolidines as potent and novel protein-protein interaction inhibitors of the PRC2 complex through EED binding},
author = {Curtin, Michael L. and Pliushchev, Marina A. and Li, Huan-Qiu and Torrent, Maricel and Dietrich, Justin D. and Jakob, Clarissa G. and Zhu, Haizhong and Zhao, Hongyu and Wang, Ying and Ji, Zhiqin and Clark, Richard F. and Sarris, Kathy A. and Selvaraju, Sujatha and Shaw, Bailin and Algire, Mikkel A. and He, Yupeng and Richardson, Paul L. and Sweis, Ramzi F. and Sun, Chaohong and Chiang, Gary G. and Michaelides, Michael R.},
abstractNote = {},
doi = {10.1016/j.bmcl.2017.02.030},
journal = {Bioorganic and Medicinal Chemistry Letters},
number = 7,
volume = 27,
place = {United States},
year = {Sat Apr 01 00:00:00 EDT 2017},
month = {Sat Apr 01 00:00:00 EDT 2017}
}
  • Polycomb repressive complex 2 (PRC2) is a regulator of epigenetic states required for development and homeostasis. PRC2 trimethylates histone H3 at lysine 27 (H3K27me3), which leads to gene silencing, and is dysregulated in many cancers. The embryonic ectoderm development (EED) protein is an essential subunit of PRC2 that has both a scaffolding function and an H3K27me3-binding function. Here we report the identification of A-395, a potent antagonist of the H3K27me3 binding functions of EED. Structural studies demonstrate that A-395 binds to EED in the H3K27me3-binding pocket, thereby preventing allosteric activation of the catalytic activity of PRC2. Phenotypic effects observed inmore » vitro and in vivo are similar to those of known PRC2 enzymatic inhibitors; however, A-395 retains potent activity against cell lines resistant to the catalytic inhibitors. A-395 represents a first-in-class antagonist of PRC2 protein–protein interactions (PPI) for use as a chemical probe to investigate the roles of EED-containing protein complexes.« less
  • 3-Hydroxyquinolin-2(1H)-one (2) was discovered by high throughput screening in a functional assay to be a potent inhibitor of human DAAO, and its binding affinity was confirmed in a Biacore assay. Cocrystallization of 2 with the human DAAO enzyme defined the binding site and guided the design of new analogues. The SAR, pharmacokinetics, brain exposure, and effects on cerebellum D-serine are described. Subsequent evaluation against the rat DAAO enzyme revealed a divergent SAR versus the human enzyme and may explain the high exposures of drug necessary to achieve significant changes in rat or mouse cerebellum D-serine.
  • 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 tomore » 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.« less
  • PRC2 is a multisubunit methyltransferase involved in epigenetic regulation of early embryonic development and cell growth. The catalytic subunit EZH2 methylates primarily lysine 27 of histone H3, leading to chromatin compaction and repression of tumor suppressor genes. Inhibiting this activity by small molecules targeting EZH2 was shown to result in antitumor efficacy. Here, we describe the optimization of a chemical series representing a new class of PRC2 inhibitors which acts allosterically via the trimethyllysine pocket of the noncatalytic EED subunit. Deconstruction of a larger and complex screening hit to a simple fragment-sized molecule followed by structure-guided regrowth and careful propertymore » modulation were employed to yield compounds which achieve submicromolar inhibition in functional assays and cellular activity. The resulting molecules can serve as a simplified entry point for lead optimization and can be utilized to study this new mechanism of PRC2 inhibition and the associated biology in detail.« less