Division of Biological Chemistry and Drug Discovery, School of Life Sciences, James Black Centre , University of Dundee , Dow Street , DD1 5EH , Dundee , Scotland , United Kingdom.
Dipartimento di Farmacia, Sezione di Chimica del Farmaco e del Prodotto Cosmetico , Università degli Studi di Genova , Viale Benedetto XV 3 , 16132 Genova , Italy.
J Med Chem. 2019 Jan 24;62(2):699-726. doi: 10.1021/acs.jmedchem.8b01413. Epub 2018 Dec 28.
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.
开发可将 E3 连接酶的泛素化活性重新导向并在细胞内有效降解靶蛋白的 PROTACs 是一个漫长而不可预测的过程，目前尚不清楚任何 E3 和靶标的组合是否可用于降解。我们描述了一种针对被认为不合适的连接酶-靶标对的探针质量降解剂：von Hippel-Lindau（VHL）和 BRD9，SWI/SNF 染色质重塑复合物 BAF 的一个含溴结构域的亚基。通过系统改变缀合模式和连接子，并监测细胞降解活性、动力学特征和泛素化以及三元复合物形成热力学，可以从次优化合物中对基于 VHL 的降解剂进行两轮优化。出现的结构-活性关系指导了 VZ185 的发现，VZ185 是 BRD9 及其密切同源物 BRD7 的有效、快速和选择性降解剂。我们的发现为 BRD7/9 的 knockdown 提供了一种新的化学工具，并为针对看似不兼容的靶标-连接酶组合的 PROTAC 开发提供了路线图。
