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)

Research output: Contribution to journalArticle

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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

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Ubiquitination
Ligases
Proteolysis
Chromatin Assembly and Disassembly
Ubiquitin-Protein Ligases
Structure-Activity Relationship
Thermodynamics
Proteins

Keywords

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

Cite this

Zoppi, Vittoria ; Hughes, Scott J. ; Maniaci, Chiara ; Testa, Andrea ; Gmaschitz, Teresa ; Wieshofer, Corinna ; Koegl, Manfred ; Riching, Kristin M. ; Daniels, Danette L. ; Spallarossa, Andrea ; Ciulli, Alessio. / 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. In: Journal of Medicinal Chemistry. 2019 ; Vol. 62, No. 2. pp. 699-726.
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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.",
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note = "This project has received funding from the European Research Council (ERC) under the European Union’s Seventh Framework Programme (FP7/2007-2013) as a Starting Grant to A.C. (grant agreement No. ERC-2012-StG-311460 DrugE3CRLs). Biophysics and drug discovery activities are supported by Wellcome Trust strategic awards to Dundee (100476/Z/12/Z and 094090/Z/10/Z, respectively). V.Z. was supported by the “Scuola di Dottorato in Scienze e Tecnologie della Chimica e dei Materiali” of the University of Genova, Italy.",
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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. / Zoppi, Vittoria; Hughes, Scott J.; Maniaci, Chiara; Testa, Andrea; Gmaschitz, Teresa; Wieshofer, Corinna; Koegl, Manfred; Riching, Kristin M.; Daniels, Danette L.; Spallarossa, Andrea; Ciulli, Alessio (Lead / Corresponding author).

In: Journal of Medicinal Chemistry, Vol. 62, No. 2, 24.01.2019, p. 699-726.

Research output: Contribution to journalArticle

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AU - Zoppi, Vittoria

AU - Hughes, Scott J.

AU - Maniaci, Chiara

AU - Testa, Andrea

AU - Gmaschitz, Teresa

AU - Wieshofer, Corinna

AU - Koegl, Manfred

AU - Riching, Kristin M.

AU - Daniels, Danette L.

AU - Spallarossa, Andrea

AU - Ciulli, Alessio

N1 - This project has received funding from the European Research Council (ERC) under the European Union’s Seventh Framework Programme (FP7/2007-2013) as a Starting Grant to A.C. (grant agreement No. ERC-2012-StG-311460 DrugE3CRLs). Biophysics and drug discovery activities are supported by Wellcome Trust strategic awards to Dundee (100476/Z/12/Z and 094090/Z/10/Z, respectively). V.Z. was supported by the “Scuola di Dottorato in Scienze e Tecnologie della Chimica e dei Materiali” of the University of Genova, Italy.

PY - 2019/1/24

Y1 - 2019/1/24

N2 - 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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KW - PROTACs

KW - protein degradation

KW - E3 ubiquitin ligases

KW - bromodomain

KW - von Hippel-Lindau

KW - BRD7

KW - BRD9

U2 - 10.1021/acs.jmedchem.8b01413

DO - 10.1021/acs.jmedchem.8b01413

M3 - Article

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VL - 62

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EP - 726

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

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