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Structure-Guided Design of EED Binders Allosterically Inhibiting the Epigenetic Methyltransferase PRC2

Lingel, Andreas and Bussiere, Dirksen and Cantwell, John and Dillon, Michael and Fu, Xingnian and Fuller, John and Gu, Justin and Huang, Ying and Jiang, Xiangqing and Li, Ling and Liang, Fang and Lindvall, Mika and Mckenna, Maureen and Qi, Vicky and Rao, Weijun and Sendzik, Martin and Sheng, Xijun and Shu, Wei and Shultz, Michael and Taft, Benjamin and Wang, Long and Zeng, Jue and Zhang, Maya and Zhang, Hailong and Zhao, Kehao and Gabriel, Tobias (2017) Structure-Guided Design of EED Binders Allosterically Inhibiting the Epigenetic Methyltransferase PRC2. Jounal of Medicinal Chemistry.

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 anti-tumor efficacy. Here, we describe the identification and optimization of a new class of small molecule PRC2 inhibitors that acts allosterically via the trimethyllysine pocket of the non-catalytic EED subunit. Deconstruction of a larger screening hit to a fragment-sized molecule followed by structure-guided regrowth and careful property modulation were employed to achieve sub-micromolar inhibition in functional assays and cellular activity.

Item Type: Article
Date Deposited: 17 Jan 2017 00:45
Last Modified: 17 Jan 2017 00:45
URI: https://oak.novartis.com/id/eprint/30383

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