Identification of Covalent Bromodomain Binders through DNA Display of Small Molecules

Angewandte Chemie
Jean-Pierre DaguerNicolas Winssinger

Abstract

The regulation of transcriptional programs by epigenetic readers (bromodomains) has been linked to the development of several pathologies. Notably, it has been implicated in the regulation of cellular growth and evasion of apoptosis, in cancer as well as in inflammation. The discovery of small-molecule probes to dissect the role of bromodomains is thus important. We demonstrate that specific cysteine residues conserved across the bromodomains can be harnessed for covalent trapping. We report the discovery of two small molecules that form a covalent bond with cysteine residues conserved across the bromodomain family, analyze the subset of bromodomains that can be addressed through covalent binding, and show proteomic analyses enabled by the enrichment of bromodomains from native lysates.

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Citations

May 8, 2015·Accounts of Chemical Research·Sofia Barluenga, Nicolas Winssinger
Feb 26, 2016·Journal of Medicinal Chemistry·Raphael M Franzini, Cassie Randolph
Aug 2, 2016·Drug Discovery Today·Gunther Zimmermann, Dario Neri
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Dec 25, 2016·Bioorganic & Medicinal Chemistry Letters·Bingbing ShiXiaoyu Li
Jun 7, 2018·SLAS Discovery·Melanie LeveridgeDarren Green
Nov 2, 2017·The Journal of Antibiotics·Roman LagoutteNicolas Winssinger
Jun 27, 2015·Beilstein Journal of Organic Chemistry·Alexandre Novoa, Nicolas Winssinger
Sep 15, 2020·Medicinal Research Reviews·Ewelina KulikowskiNorman C W Wong
May 22, 2019·Expert Opinion on Drug Discovery·Guixian ZhaoXiaoyu Li
Dec 10, 2020·ChemMedChem·Verena B K KunigAndreas Brunschweiger
Dec 23, 2015·Bioorganic & Medicinal Chemistry Letters·Sofia BarluengaNicolas Winssinger
Jun 14, 2017·Current Opinion in Chemical Biology·Roman LagoutteNicolas Winssinger
Apr 24, 2021·Chembiochem : a European Journal of Chemical Biology·Yiran Huang, Xiaoyu Li
Jul 4, 2021·Bioorganic & Medicinal Chemistry·Jean-Pierre DaguerNicolas Winssinger
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Dec 4, 2019·ACS Chemical Biology·Ainoa Figuerola-ConchasMonica Gotta
Jul 12, 2017·Journal of the American Chemical Society·Alix I ChanDavid R Liu

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