溴尿嘧啶
化学
泛素
三元络合物
蛋白酶体
泛素连接酶
DNA连接酶
蛋白质水解
染色质重塑
蛋白质亚单位
癌症研究
计算生物学
细胞生物学
生物化学
染色质
DNA
生物
酶
组蛋白
基因
作者
Vittoria Zoppi,Scott J. Hughes,Chiara Maniaci,Andrea Testa,Teresa Gmaschitz,Corinna Wieshofer,Manfred Koegl,Kristin M. Riching,Danette L. Daniels,Andrea Spallarossa,A. Ciulli
标识
DOI:10.1021/acs.jmedchem.8b01413
摘要
Developing PROTACs to redirect the ubiquitination activity of E3 ligases and potently degrade a target protein within cells can be a lengthy and unpredictable process, and it remains unclear whether any combination of E3 and target might be productive for degradation. We describe a probe-quality degrader for a ligase-target pair deemed unsuitable: the von Hippel-Lindau (VHL) and BRD9, a bromodomain-containing subunit of the SWI/SNF chromatin remodeling complex BAF. VHL-based degraders could be optimized from suboptimal compounds in two rounds by systematically varying conjugation patterns and linkers and monitoring cellular degradation activities, kinetic profiles, and ubiquitination, as well as ternary complex formation thermodynamics. The emerged structure-activity relationships guided the discovery of VZ185, a potent, fast, and selective degrader of BRD9 and of its close homolog BRD7. Our findings qualify a new chemical tool for BRD7/9 knockdown and provide a roadmap for PROTAC development against seemingly incompatible target-ligase combinations.
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