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DCAF1-based PROTACs with activity against clinically validated targets overcoming intrinsic- and acquired-degrader resistance

Author

Listed:
  • Martin Schröder

    (Novartis Institutes for BioMedical Research)

  • Martin Renatus

    (Novartis Institutes for BioMedical Research
    Ridgeline Discovery)

  • Xiaoyou Liang

    (Novartis Institutes for BioMedical Research)

  • Fabian Meili

    (Novartis Institutes for BioMedical Research)

  • Thomas Zoller

    (Novartis Institutes for BioMedical Research)

  • Sandrine Ferrand

    (Novartis Institutes for BioMedical Research)

  • Francois Gauter

    (Novartis Institutes for BioMedical Research)

  • Xiaoyan Li

    (Novartis Institutes for BioMedical Research)

  • Frederic Sigoillot

    (Novartis Institutes for BioMedical Research)

  • Scott Gleim

    (Novartis Institutes for BioMedical Research)

  • Therese-Marie Stachyra

    (Novartis Institutes for BioMedical Research)

  • Jason R. Thomas

    (Novartis Institutes for BioMedical Research)

  • Damien Begue

    (Novartis Institutes for BioMedical Research)

  • Maryam Khoshouei

    (Novartis Institutes for BioMedical Research)

  • Peggy Lefeuvre

    (Novartis Institutes for BioMedical Research)

  • Rita Andraos-Rey

    (Novartis Institutes for BioMedical Research)

  • BoYee Chung

    (Novartis Institutes for BioMedical Research)

  • Renate Ma

    (Novartis Institutes for BioMedical Research)

  • Benika Pinch

    (Novartis Institutes for BioMedical Research)

  • Andreas Hofmann

    (Novartis Institutes for BioMedical Research)

  • Markus Schirle

    (Novartis Institutes for BioMedical Research)

  • Niko Schmiedeberg

    (Novartis Institutes for BioMedical Research)

  • Patricia Imbach

    (Novartis Institutes for BioMedical Research)

  • Delphine Gorses

    (Novartis Institutes for BioMedical Research)

  • Keith Calkins

    (Novartis Institutes for BioMedical Research)

  • Beatrice Bauer-Probst

    (Novartis Institutes for BioMedical Research)

  • Magdalena Maschlej

    (Novartis Institutes for BioMedical Research)

  • Matt Niederst

    (Novartis Institutes for BioMedical Research)

  • Rob Maher

    (Novartis Institutes for BioMedical Research)

  • Martin Henault

    (Novartis Institutes for BioMedical Research)

  • John Alford

    (Novartis Institutes for BioMedical Research)

  • Erik Ahrne

    (Novartis Institutes for BioMedical Research)

  • Luca Tordella

    (Novartis Institutes for BioMedical Research)

  • Greg Hollingworth

    (Novartis Institutes for BioMedical Research)

  • Nicolas H. Thomä

    (Friedrich Miescher Institute for Biomedical Research
    École Polytechnique Fédérale de Lausanne)

  • Anna Vulpetti

    (Novartis Institutes for BioMedical Research)

  • Thomas Radimerski

    (Novartis Institutes for BioMedical Research
    Ridgeline Discovery)

  • Philipp Holzer

    (Novartis Institutes for BioMedical Research)

  • Seth Carbonneau

    (Novartis Institutes for BioMedical Research)

  • Claudio R. Thoma

    (Novartis Institutes for BioMedical Research
    Ridgeline Discovery)

Abstract

Targeted protein degradation (TPD) mediates protein level through small molecule induced redirection of E3 ligases to ubiquitinate neo-substrates and mark them for proteasomal degradation. TPD has recently emerged as a key modality in drug discovery. So far only a few ligases have been utilized for TPD. Interestingly, the workhorse ligase CRBN has been observed to be downregulated in settings of resistance to immunomodulatory inhibitory drugs (IMiDs). Here we show that the essential E3 ligase receptor DCAF1 can be harnessed for TPD utilizing a selective, non-covalent DCAF1 binder. We confirm that this binder can be functionalized into an efficient DCAF1-BRD9 PROTAC. Chemical and genetic rescue experiments validate specific degradation via the CRL4DCAF1 E3 ligase. Additionally, a dasatinib-based DCAF1 PROTAC successfully degrades cytosolic and membrane-bound tyrosine kinases. A potent and selective DCAF1-BTK-PROTAC (DBt-10) degrades BTK in cells with acquired resistance to CRBN-BTK-PROTACs while the DCAF1-BRD9 PROTAC (DBr-1) provides an alternative strategy to tackle intrinsic resistance to VHL-degrader, highlighting DCAF1-PROTACS as a promising strategy to overcome ligase mediated resistance in clinical settings.

Suggested Citation

  • Martin Schröder & Martin Renatus & Xiaoyou Liang & Fabian Meili & Thomas Zoller & Sandrine Ferrand & Francois Gauter & Xiaoyan Li & Frederic Sigoillot & Scott Gleim & Therese-Marie Stachyra & Jason R., 2024. "DCAF1-based PROTACs with activity against clinically validated targets overcoming intrinsic- and acquired-degrader resistance," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-023-44237-4
    DOI: 10.1038/s41467-023-44237-4
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    1. David Schwefel & Harriet C. T. Groom & Virginie C. Boucherit & Evangelos Christodoulou & Philip A. Walker & Jonathan P. Stoye & Kate N. Bishop & Ian A. Taylor, 2014. "Structural basis of lentiviral subversion of a cellular protein degradation pathway," Nature, Nature, vol. 505(7482), pages 234-238, January.
    2. Danny T. Huang & Harold W. Hunt & Min Zhuang & Melanie D. Ohi & James M. Holton & Brenda A. Schulman, 2007. "Basis for a ubiquitin-like protein thioester switch toggling E1–E2 affinity," Nature, Nature, vol. 445(7126), pages 394-398, January.
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    Cited by:

    1. Daniel C. Scott & Suresh Dharuman & Elizabeth Griffith & Sergio C. Chai & Jarrid Ronnebaum & Moeko T. King & Rajendra Tangallapally & Chan Lee & Clifford T. Gee & Lei Yang & Yong Li & Victoria C. Loud, 2024. "Principles of paralog-specific targeted protein degradation engaging the C-degron E3 KLHDC2," Nature Communications, Nature, vol. 15(1), pages 1-19, December.

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