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Title: Structure-Guided Design of EED Binders Allosterically Inhibiting the Epigenetic Polycomb Repressive Complex 2 (PRC2) Methyltransferase

Abstract

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 property modulation were employed to yield compounds which achieve submicromolar inhibition in functional assays and cellular activity. Furthermore, 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.

Authors:
ORCiD logo [1];  [2]; ORCiD logo [3];  [4];  [5];  [6];  [3];  [5];  [7];  [3];  [3];  [3];  [3];  [5];  [3];  [3];  [3];  [5];  [6];  [5] more »;  [3];  [3];  [8];  [3];  [4];  [5];  [5] « less
+ Show Author Affiliations
  1. Novartis Inst. for BioMedical Research, Emeryville, CA (United States); Novartis Inst. for BioMedical Research, Basel (Switzerland)
  2. Novartis Inst. for BioMedical Research, Emeryville, CA (United States); Novartis Inst. for BioMedical Research, Cambridge, MA (United States)
  3. Novartis Inst. for BioMedical Research, Shanghai (China)
  4. Novartis Inst. for BioMedical Research, Shanghai (China); Novartis Inst. for BioMedical Research, Cambridge, MA (United States)
  5. Novartis Inst. for BioMedical Research, Emeryville, CA (United States)
  6. Novartis Inst. for BioMedical Research, Emeryville, CA (United States); Ideaya Biosciences, South San Francisco, CA (United States)
  7. Novartis Inst. for BioMedical Research, Shanghai (China); Novartis Inst. for BioMedical Research, Basel (Switzerland)
  8. Novartis Inst. for BioMedical Research, Shanghai (China); Array BioPharma, Boulder, CO (United States)
Publication Date:
Research Org.:
Argonne National Laboratory (ANL), Argonne, IL (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Basic Energy Sciences (BES)
OSTI Identifier:
1405000
Grant/Contract Number:  
AC02-05CH11231
Resource Type:
Accepted Manuscript
Journal Name:
Journal of Medicinal Chemistry
Additional Journal Information:
Journal Volume: 60; Journal Issue: 1; Journal ID: ISSN 0022-2623
Publisher:
American Chemical Society (ACS)
Country of Publication:
United States
Language:
ENGLISH
Subject:
60 APPLIED LIFE SCIENCES; 37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY; peptides and proteins; monomers; molecules; inhibitors; aromatic compounds; epigenetics; allosteric inhibition; fragment-based lead generation; oncology; EED; PRC2

Citation Formats

Lingel, Andreas, Sendzik, Martin, Huang, Ying, Shultz, Michael D., Cantwell, John, Dillon, Michael P., Fu, Xingnian, Fuller, John, Gabriel, Tobias, Gu, Justin, Jiang, Xiangqing, Li, Ling, Liang, Fang, McKenna, Maureen, Qi, Wei, Rao, Weijun, Sheng, Xijun, Shu, Wei, Sutton, James, Taft, Benjamin, Wang, Long, Zeng, Jue, Zhang, Hailong, Zhang, Maya, Zhao, Kehao, Lindvall, Mika, and Bussiere, Dirksen E. Structure-Guided Design of EED Binders Allosterically Inhibiting the Epigenetic Polycomb Repressive Complex 2 (PRC2) Methyltransferase. United States: N. p., 2016. Web. doi:10.1021/acs.jmedchem.6b01473.
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Lingel, Andreas, Sendzik, Martin, Huang, Ying, Shultz, Michael D., Cantwell, John, Dillon, Michael P., Fu, Xingnian, Fuller, John, Gabriel, Tobias, Gu, Justin, Jiang, Xiangqing, Li, Ling, Liang, Fang, McKenna, Maureen, Qi, Wei, Rao, Weijun, Sheng, Xijun, Shu, Wei, Sutton, James, Taft, Benjamin, Wang, Long, Zeng, Jue, Zhang, Hailong, Zhang, Maya, Zhao, Kehao, Lindvall, Mika, & Bussiere, Dirksen E. Structure-Guided Design of EED Binders Allosterically Inhibiting the Epigenetic Polycomb Repressive Complex 2 (PRC2) Methyltransferase. United States. https://doi.org/10.1021/acs.jmedchem.6b01473
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Lingel, Andreas, Sendzik, Martin, Huang, Ying, Shultz, Michael D., Cantwell, John, Dillon, Michael P., Fu, Xingnian, Fuller, John, Gabriel, Tobias, Gu, Justin, Jiang, Xiangqing, Li, Ling, Liang, Fang, McKenna, Maureen, Qi, Wei, Rao, Weijun, Sheng, Xijun, Shu, Wei, Sutton, James, Taft, Benjamin, Wang, Long, Zeng, Jue, Zhang, Hailong, Zhang, Maya, Zhao, Kehao, Lindvall, Mika, and Bussiere, Dirksen E. Mon . "Structure-Guided Design of EED Binders Allosterically Inhibiting the Epigenetic Polycomb Repressive Complex 2 (PRC2) Methyltransferase". United States. https://doi.org/10.1021/acs.jmedchem.6b01473. https://www.osti.gov/servlets/purl/1405000.
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@article{osti_1405000,
title = {Structure-Guided Design of EED Binders Allosterically Inhibiting the Epigenetic Polycomb Repressive Complex 2 (PRC2) Methyltransferase},
author = {Lingel, Andreas and Sendzik, Martin and Huang, Ying and Shultz, Michael D. and Cantwell, John and Dillon, Michael P. and Fu, Xingnian and Fuller, John and Gabriel, Tobias and Gu, Justin and Jiang, Xiangqing and Li, Ling and Liang, Fang and McKenna, Maureen and Qi, Wei and Rao, Weijun and Sheng, Xijun and Shu, Wei and Sutton, James and Taft, Benjamin and Wang, Long and Zeng, Jue and Zhang, Hailong and Zhang, Maya and Zhao, Kehao and Lindvall, Mika and Bussiere, Dirksen E.},
abstractNote = {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 property modulation were employed to yield compounds which achieve submicromolar inhibition in functional assays and cellular activity. Furthermore, 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.},
doi = {10.1021/acs.jmedchem.6b01473},
journal = {Journal of Medicinal Chemistry},
number = 1,
volume = 60,
place = {United States},
year = {Mon Dec 19 00:00:00 EST 2016},
month = {Mon Dec 19 00:00:00 EST 2016}
}
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https://doi.org/10.1021/acs.jmedchem.6b01473
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    Works referencing / citing this record:

    The Promise for Histone Methyltransferase Inhibitors for Epigenetic Therapy in Clinical Oncology: A Narrative Review
    journal, May 2020

    Lineage specification and pluripotency revealed by transcriptome analysis from oocyte to blastocyst in pig
    journal, November 2019

    Enhancer of zeste homolog 2 (EZH2) inhibitors
    journal, December 2017

    MEP50/PRMT5-mediated methylation activates GLI1 in Hedgehog signalling through inhibition of ubiquitination by the ITCH/NUMB complex
    journal, January 2019

    Binding Modes of Small‐Molecule Inhibitors to the EED Pocket of PRC2
    journal, January 2020

    EZH2 inhibitors: a patent review (2014-2016)
    journal, April 2017

    EZH2 inhibitors: a patent review (2014-2016)
    text, January 2017

    Inhibitors of Protein Methyltransferases and Demethylases
    journal, March 2017

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