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The EED protein–protein interaction inhibitor A-395 inactivates the PRC2 complex

Nature Chemical Biology volume 13, pages 389–395 (2017)Cite this article

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An Erratum to this article was published on 18 July 2017

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Abstract

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 in 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.

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Figure 1: A-395 is a potent binder of the EED protein that inhibits the enzymatic activity of PRC2.
Figure 2: Crystal Structure of A-395 bound to EED.
Figure 3: A-395 inhibits activity of PRC2 in cells.
Figure 4: In vivo antitumor activity of A-395 in the DLBCL Pfeiffer xenograft model.
Figure 5: Karpas422 cells with acquired resistance to the EZH2 small-molecule inhibitor GSK126 are not cross-resistant to the EED inhibitor A-395.

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  • 14 June 2017

    In the version of this article initially published, the keys for the graphs in Figure 5b–e incorrectly stated GDK126 instead of GSK126. The error has been corrected in the HTML and PDF versions of the article.

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Acknowledgements

The authors would like to thank P. Richardson, Y. Wang, H. Zhao, R. Clark, and Z. Ji for chemistry support. Thanks to S. Duan, S. Kakavas and R. Edalji for biochemistry and biophysics support. We would also like to thank K. Bromberg and L. Lasko for designing and helping interpret the high-content analysis assay and B. Ainsworth for help with data analysis and graphing. Finally, we would like to thank E. Nicholl, T. Shah, J. Trumbull, X. Cao, and Q. Lang for valuable assistance in TSA method development and high-throughput screening. E.L-F. is the recipient of a Canadian Institutes of Health Research Banting Postdoctoral Fellowship. Use of the IMCA-CAT beamline 17-ID at the Advanced Photon Source was supported by the companies of the Industrial Macromolecular Crystallography Association through a contract with Hauptman–Woodward Medical Research Institute. This research used resources of the Advanced Photon Source, a US Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory under Contract No. DE-AC02-06CH11357. The SGC is a registered charity (number 1097737) that receives funds from AbbVie, Bayer Pharma AG, Boehringer Ingelheim, the Canada Foundation for Innovation, the Eshelman Institute for Innovation, Genome Canada through the Ontario Genomics Institute, Innovative Medicines Initiative (EU/EFPIA) (ULTRA-DD grant no. 115766), Janssen, Merck & Co., Novartis Pharma AG, the Ontario Ministry of Economic Development and Innovation, Pfizer, the São Paulo Research Foundation-FAPESP, Takeda, and the Wellcome Trust.

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Authors and Affiliations

  1. AbbVie Inc., North Chicago, Illinois, USA

    Yupeng He, Sujatha Selvaraju, Michael L Curtin, Clarissa G Jakob, Haizhong Zhu, Kenneth M Comess, Bailin Shaw, Dong Cheng, Kelly L Klinge, Huan-Qiu Li, Marina Pliushchev, Mikkel A Algire, David Maag, Jun Guo, Justin Dietrich, Sanjay C Panchal, Andrew M Petros, Ramzi F Sweis, Maricel Torrent, Lance J Bigelow, Donald J Osterling, David J Lindley, Wenqing Gao, Scott Galasinski, Fritz G Buchanan, Gary G Chiang, Chaohong Sun & William N Pappano

  2. Structural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada

    Juliana The, Evelyne Lima-Fernandes, Magdalena M Szewczyk, Guillermo Senisterra, Fengling Li, Steven Kennedy, Qin Wu, Dalia Barsyte-Lovejoy, Masoud Vedadi & Cheryl H Arrowsmith

  3. and Department of Medical Biophysics, Princess Margaret Cancer Centre, University of Toronto, Toronto, Ontario, Canada

    Evelyne Lima-Fernandes, Qin Wu & Cheryl H Arrowsmith

  4. Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada

    Masoud Vedadi

  5. eFFECTOR Therapeutics, San Diego, California, USA

    Gary G Chiang

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Contributions

K.M.C. and S.G. developed and conducted the high-throughput screen. M.L.C., R.F.S., H.-Q.L., M.P., and J.D. designed compounds. J.T., F.L., S.K., and G.S. performed binding, activity and selectivity. Y.H., S.S., J.G., E.L.-F., M.M.S., and Q.W. performed AlphaLISA, cell proliferation, colony formation, drug resistance selection and characterization, western blotting assays, and data analyses. K.L.K. performed high-content microscopy cellular methyl mark assays. A.M.P. and S.C.P. performed biophysical measurements aimed at characterizing compound binding to EED. M.T. generated small-molecule docking/computational models. H.Z. and L.J.B. produced protein and protein crystals and C.G.J. performed X-ray structure determination and analysis. B.S., M.A.A., and D.M. designed and performed in vitro biochemical studies. D.J.O and D.J.L performed drug formulation studies and pharmacokinetic analysis. D.C. performed in vivo studies. M.V. designed experiments, reviewed data and led in vitro assays. Y.H., W.G., D.B.-L., F.G.B., C.H.A., G.G.C., C.S., and W.N.P. designed studies and interpreted results. W.N.P. wrote the paper.

Corresponding authors

Correspondence to Chaohong Sun or William N Pappano.

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Competing interests

This study was sponsored by AbbVie. AbbVie contributed to the study design, research, interpretation of data, writing, reviewing, and approval of the publication. Y.H., S.S., M.L.C., C.G.J., H.Z., K.M.C., B.S., D.C., K.L.K., H.-Q.L., M.P., M.A.A., D.M., J.G., J.D., S.C.P., A.M.P., R.F.S., M.T., L.J.B., D.J.O., D.J.L., W.G., S.G., F.G.B., G.G.C., C.S., and W.N.P. were employees of AbbVie at the time of the study.

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He, Y., Selvaraju, S., Curtin, M. et al. The EED protein–protein interaction inhibitor A-395 inactivates the PRC2 complex. Nat Chem Biol 13, 389–395 (2017). https://doi.org/10.1038/nchembio.2306

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