Discovery of a novel B-cell lymphoma 6 (BCL6)–corepressor interaction inhibitor by utilizing structure-based drug design

Takeshi Yasui; Takeshi Yamamoto; Nozomu SakaiKouhei AsanoTakafumi TakaiYayoi YoshitomiMelinda DavisTerufumi TakagiKotaro SakamotoSatoshi SogabeYusuke KamadaWeston LaneGyorgy SnellMasashi IwataMasayuki GotoHiroshi InookaJun-ichi SakamotoYoshihisa NakadaYasuhiro Imaeda

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Discovery of a novel B-cell lymphoma 6 (BCL6)–corepressor interaction inhibitor by utilizing structure-based drug design

机译：Discovery of a novel B-cell lymphoma 6 (BCL6)–corepressor interaction inhibitor by utilizing structure-based drug design

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Graphical abstract Display Omitted Abstract B-cell lymphoma 6 (BCL6) is a transcriptional repressor that can form complexes with corepressors via protein–protein interactions (PPIs). The complexes of BCL6 and corepressors play an important role in the formation of germinal centers (GCs), and differentiation and proliferation of lymphocytes. Therefore, BCL6–corepressor interaction inhibitors would be drug candidates for managing autoimmune diseases and cancer. Starting from high-throughput screening hits 1a and 2a , we identified a novel BCL6–corepressor interaction inhibitor 8c (cell-free enzyme-linked immunosorbent assay ELISA IC 50 = 0.10 μM, cell-based mammalian two-hybrid M2H assay IC 50 = 0.72 μM) by utilizing structure-based drug design (SBDD) based on an X-ray crystal structure of 1a bound to BCL6. Compound 8c also showed a good pharmacokinetic profile, which was acceptable for both in vitro and in vivo studies. >

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《Bioorganic and medicinal chemistry》 |2017年第17期|4876-4886|共11页
作者
Takeshi Yasui; Takeshi Yamamoto; Nozomu SakaiKouhei AsanoTakafumi TakaiYayoi YoshitomiMelinda DavisTerufumi TakagiKotaro SakamotoSatoshi SogabeYusuke KamadaWeston LaneGyorgy SnellMasashi IwataMasayuki GotoHiroshi InookaJun-ichi SakamotoYoshihisa NakadaYasuhiro Imaeda;
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Takeda Pharmaceutical Company Limited;

Takeda California Inc.;

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原文格式 PDF
正文语种英语
中图分类药学;
关键词
B cell lymphoma 6 (BCL6); Protein–protein interaction (PPI); Structure-based drug design (SBDD); Diphenylamine;

Discovery of a novel B-cell lymphoma 6 (BCL6)–corepressor interaction inhibitor by utilizing structure-based drug design

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