- Structure-Guided Design of EED Binders Allosterically Inhibiting the Epigenetic Polycomb Repressive Complex 2 (PRC2) Methyltransferase
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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.
- 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.
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supporting information
p. 415 - 427
(2017/04/26)
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- PYRIDINONE DICARBOXAMIDE FOR USE AS BROMODOMAIN INHIBITORS
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The present invention relates to compounds of formula (I) and salts thereof, pharmaceutical compositions containing such compounds and to their use in therapy.
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Page/Page column 74
(2017/03/21)
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- Novel 4-phenyl substituted tetrahydroisoquinolines and therapeutic use thereof
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The present invention relates to a method of treating disorders including cognition impairment, generalized anxiety disorder, acute stress disorder, social phobia, simple phobias, pre-menstrual dysphoric disorder, social anxiety disorder, major depressive
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Page/Page column 10; 16
(2010/11/08)
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- A facile synthesis of [14C]enadoline [(5R)-(5α,7α,8β)]-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxospiro[4,5] dec-8-yl]-4-benzofuranacetamide
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4-Chloromethylbenzofuran (10) was synthesized from 2,3-dimethylanisole in 7 steps. The corresponding Grignard reagent prepared from magnesium anthracene complex reacts with 14CO2, SOCl2, and PD130812 successively to give [
- Pu,Scripko,Huang
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p. 1183 - 1191
(2007/10/03)
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