Iterative design and optimization of initially inactive Proteolysis Targeting Chimeras (PROTACs) identify VZ185 as a potent, fast and selective von Hippel-Lindau (VHL)-based dual degrader probe of BRD9 and BRD7

Vittoria Zoppi, Scott J. Hughes, Chiara Maniaci, Andrea Testa, Teresa Gmaschitz, Corinna Wieshofer, Manfred Koegl, Kristin M. Riching, Danette L. Daniels, Andrea Spallarossa, Alessio Ciulli (Lead / Corresponding author)

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Abstract

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.
Original languageEnglish
Pages (from-to)699-726
Number of pages28
JournalJournal of Medicinal Chemistry
Volume62
Issue number2
Early online date12 Dec 2018
DOIs
Publication statusPublished - 24 Jan 2019

Keywords

  • PROTACs
  • protein degradation
  • E3 ubiquitin ligases
  • bromodomain
  • von Hippel-Lindau
  • BRD7
  • BRD9

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