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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. 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:
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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:
1405000
Resource Type:
Journal Article
Resource Relation:
Journal Name: Journal of Medicinal Chemistry; Journal Volume: 60; Journal Issue: 1
Country of Publication:
United States
Language:
ENGLISH
Subject:
60 APPLIED LIFE SCIENCES; 37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY

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., 2017. Web. doi:10.1021/acs.jmedchem.6b01473.
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. doi:10.1021/acs.jmedchem.6b01473.
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. Thu . "Structure-Guided Design of EED Binders Allosterically Inhibiting the Epigenetic Polycomb Repressive Complex 2 (PRC2) Methyltransferase". United States. doi:10.1021/acs.jmedchem.6b01473.
@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. 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 = {Thu Jan 12 00:00:00 EST 2017},
month = {Thu Jan 12 00:00:00 EST 2017}
}