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Lookup NU author(s): Dr Chiara ManiaciORCiD
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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.
Author(s): Zoppi V, Hughes SJ, Maniaci C, Testa A, Gmaschitz T, Wieshofer C, Koegl M, Riching K, Daniels D, Spallarossa A, Ciulli A
Publication type: Article
Publication status: Published
Journal: Journal of Medicinal Chemistry
Year: 2018
Volume: 62
Issue: 2
Pages: 699-726
Print publication date: 24/01/2019
Online publication date: 12/12/2018
Acceptance date: 12/12/2019
ISSN (print): 0022-2623
ISSN (electronic): 1520-4804
Publisher: American Chemical Society
URL: https://doi.org/10.1021/acs.jmedchem.8b01413
DOI: 10.1021/acs.jmedchem.8b01413
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