2. Academic Validation
  3. 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

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

  • J Med Chem. 2019 Jan 24;62(2):699-726. doi: 10.1021/acs.jmedchem.8b01413.
Vittoria Zoppi 1 2,  Scott J Hughes 1,  Chiara Maniaci 1 3,  Andrea Testa 1,  Teresa Gmaschitz 4,  Corinna Wieshofer 4,  Manfred Koegl 4,  Kristin M Riching 5,  Danette L Daniels 5,  Andrea Spallarossa 2,  Alessio Ciulli 1
Affiliations

Affiliations

  • 1 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.
  • 2 Dipartimento di Farmacia, Sezione di Chimica del Farmaco e del Prodotto Cosmetico , Università degli Studi di Genova , Viale Benedetto XV 3 , 16132 Genova , Italy.
  • 3 Medical Research Council Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, James Black Centre , University of Dundee , Dow Street , DD1 5EH , Dundee , Scotland , United Kingdom.
  • 4 Boehringer Ingelheim RCV GmbH & Co. KG , 1221 Vienna , Austria.
  • 5 Promega Corporation , 2800 Woods Hollow Road , Madison , Wisconsin 53711 , United States.
PMID: 30540463 DOI: 10.1021/acs.jmedchem.8b01413
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.

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