- Structure-Guided Development of Small-Molecule PRC2 Inhibitors Targeting EZH2-EED Interaction
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Disruption of EZH2-embryonic ectoderm development (EED) protein-protein interaction (PPI) is a new promising cancer therapeutic strategy. We have previously reported the discovery of astemizole, a small-molecule inhibitor targeting the EZH2-EED PPI. Herein, we report the cocrystal structure of EED in complex with astemizole at 2.15 ?. The structure elucidates the detailed binding mode of astemizole to EED and provides a structure-guided design for the discovery of a novel EZH2-EED interaction inhibitor, DC-PRC2in-01, with an affinityKdof 4.56 μM. DC-PRC2in-01 destabilizes the PRC2 complex, thereby leading to the degradation of PRC2 core proteins and the decrease of global H3K27me3 levels in cancer cells. The proliferation of PRC2-driven lymphomas cells is effectively inhibited, and the cell cycle is arrested in the G0/G1 phase. Together, these data demonstrate that DC-PRC2in-01 could be an effective chemical probe for investigating the PRC2-related physiology and pathology and providing a promising chemical scaffold for further development.
- Du, Daohai,Xu, Dandan,Zhu, Licheng,Stazi, Giulia,Zwergel, Clemens,Liu, Yanli,Luo, Zhongyuan,Li, Yuanqing,Zhang, Yuanyuan,Zhu, Kongkai,Ding, Yiluan,Liu, Jingqiu,Fan, Shijie,Zhao, Kaiyan,Zhang, Naixia,Kong, Xiangqian,Jiang, Hualiang,Chen, Kaixian,Zhao, Kehao,Valente, Sergio,Min, Jinrong,Duan, Wenhu,Luo, Cheng
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supporting information
p. 8194 - 8207
(2021/06/28)
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- Opioid ligands with mixed properties from substituted enantiomeric N-phenethyl-5-phenylmorphans. Synthesis of a -agonist δ-antagonist and δ-inverse agonists
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Enantiomeric N-phenethyl-m-hydroxyphenylmorphans with various substituents in the ortho, meta or para positions of the aromatic ring in the phenethylamine side-chain (chloro, hydroxy, methoxy, nitro, methyl), as well as a pyridylethyl and a indolylethyl m
- Cheng, Kejun,Kim, In Jong,Lee, Mei-Jing,Adah, Steven A.,Raymond, Tyler J.,Bilsky, Edward J.,Aceto, Mario D.,May, Everette L.,Harris, Louis S.,Coop, Andrew,Dersch, Christina M.,Rothman, Richard B.,Jacobson, Arthur E.,Rice, Kenner C.
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p. 1177 - 1190
(2008/02/04)
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- Combination preparation of estrogen and anti-estrogen
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The invention describes a combination preparation of an oestrogen and an antioestrogen, characterized in that the oestrogen is selected from the group consisting of 17-β-oestradiol, 17-α-ethynyloestradiol, oestriol, oestrone, oestrone sulphate, oestrogen sulphamates, 17α-oestradiol, mestranol, stilboestrol and naturally conjugated oestrogens and in that the antioestrogen is a substituted 7α-(ξ-aminoalkyl)oestratriene of the general formula I The combination preparation according to the invention can be used for hormone substitution therapy.
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- Synthesis of N-substituted 9-azabicyclo[3.3.1]nonan-3α-yl phenylcarbamate analogs as sigma-2 receptor ligands
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Aseries of N-substituted-9-azabicyclo[3.3.1]nonan-3α-yl)carbamate analogs was prepared and their affinities for sigma (σ1 and σ2) receptors was measured in vitro. The results of this structure-activity relationship study identified a
- Mach, Robert H.,Vangveravong, Suwanna,Huang, Yunsheng,Yang, Biao,Blair, Joseph B.,Wu, Li
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p. 380 - 398
(2007/10/03)
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