Academic Journal
LP99: Discovery and Synthesis of the First Selective BRD7/9 Bromodomain Inhibitor
| العنوان: | LP99: Discovery and Synthesis of the First Selective BRD7/9 Bromodomain Inhibitor |
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| المؤلفون: | Clark, Peter G. K., Vieira, Lucas C. C., Tallant, Cynthia, Fedorov, Oleg, Singleton, Dean C., Rogers, Catherine M., Monteiro, Octovia P., Bennett, James M., Baronio, Roberta, Müller, Susanne, Daniels, Danette L., Méndez, Jacqui, Knapp, Stefan, Brennan, Paul E., Dixon, Darren J. |
| المصدر: | Angewandte Chemie ; volume 127, issue 21, page 6315-6319 ; ISSN 0044-8249 1521-3757 |
| بيانات النشر: | Wiley |
| سنة النشر: | 2015 |
| المجموعة: | Wiley Online Library (Open Access Articles via Crossref) |
| الوصف: | The bromodomain‐containing proteins BRD9 and BRD7 are part of the human SWI/SNF chromatin‐remodeling complexes BAF and PBAF. To date, no selective inhibitor for BRD7/9 has been reported despite its potential value as a biological tool or as a lead for future therapeutics. The quinolone‐fused lactam LP99 is now reported as the first potent and selective inhibitor of the BRD7 and BRD9 bromodomains. Development of LP99 from a fragment hit was expedited through balancing structure‐based inhibitor design and biophysical characterization against tractable chemical synthesis: Complexity‐building nitro‐Mannich/lactamization cascade processes allowed for early structure–activity relationship studies whereas an enantioselective organocatalytic nitro‐Mannich reaction enabled the synthesis of the lead scaffold in enantioenriched form and on scale. This epigenetic probe was shown to inhibit the association of BRD7 and BRD9 to acetylated histones in vitro and in cells. Moreover, LP99 was used to demonstrate that BRD7/9 plays a role in regulating pro‐inflammatory cytokine secretion. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | German |
| DOI: | 10.1002/ange.201501394 |
| الاتاحة: | http://dx.doi.org/10.1002/ange.201501394 https://api.wiley.com/onlinelibrary/tdm/v1/articles/10.1002%2Fange.201501394 https://onlinelibrary.wiley.com/doi/pdf/10.1002/ange.201501394 |
| Rights: | http://onlinelibrary.wiley.com/termsAndConditions#vor |
| رقم الانضمام: | edsbas.CD38187C |
| قاعدة البيانات: | BASE |
| DOI: | 10.1002/ange.201501394 |
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