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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

DOI: 10.1021/acs.jmedchem.8b01413 DOI Help

Authors: Vittoria Zoppi (University of Dundee; Sezione di Chimica del Farmaco e del Prodotto Cosmetico) , Scott J. Hughes (University of Dundee) , Chiara Maniaci (University of Dundee) , Andrea Testa (University of Dundee) , Teresa Gmaschitz (Boehringer Ingelheim RCV GmbH & Co KG) , Corinna Wieshofer (Boehringer Ingelheim RCV GmbH & Co KG) , Manfred Koegl (Boehringer Ingelheim RCV GmbH & Co KG) , Kristin Riching (Promega Corporation) , Danette L. Daniels (Promega Corporation) , Andrea Spallarossa (Sezione di Chimica del Farmaco e del Prodotto Cosmetico) , Alessio Ciulli (University of Dundee)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Journal Of Medicinal Chemistry

State: Published (Approved)
Published: December 2018
Diamond Proposal Number(s): 14980

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.

Journal Keywords: PROTACs; protein degradation; E3 ubiquitin ligases; bromodomain; von Hippel-Lindau; BRD7; BRD9

Subject Areas: Chemistry, Medicine


Instruments: I24-Microfocus Macromolecular Crystallography