2. Academic Validation
  3. DCAF1-based PROTACs with activity against clinically validated targets overcoming intrinsic- and acquired-degrader resistance

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

  • Nat Commun. 2024 Jan 4;15(1):275. doi: 10.1038/s41467-023-44237-4.
Martin Schröder # 1,  Martin Renatus # 2 3,  Xiaoyou Liang 4,  Fabian Meili 4,  Thomas Zoller 2,  Sandrine Ferrand 2,  Francois Gauter 2,  Xiaoyan Li 4,  Frederic Sigoillot 4,  Scott Gleim 4,  Therese-Marie Stachyra 2,  Jason R Thomas 4,  Damien Begue 2,  Maryam Khoshouei 2,  Peggy Lefeuvre 2,  Rita Andraos-Rey 2,  BoYee Chung 4,  Renate Ma 4,  Benika Pinch 4,  Andreas Hofmann 2,  Markus Schirle 4,  Niko Schmiedeberg 2,  Patricia Imbach 2,  Delphine Gorses 2,  Keith Calkins 2,  Beatrice Bauer-Probst 2,  Magdalena Maschlej 2,  Matt Niederst 4,  Rob Maher 4,  Martin Henault 4,  John Alford 4,  Erik Ahrne 2,  Luca Tordella 2,  Greg Hollingworth 2,  Nicolas H Thomä 5 6,  Anna Vulpetti 2,  Thomas Radimerski 2 3,  Philipp Holzer 2,  Seth Carbonneau 4,  Claudio R Thoma 7 8
Affiliations

Affiliations

  • 1 Novartis Institutes for BioMedical Research, Basel, Switzerland. martin-1.schroeder@novartis.com.
  • 2 Novartis Institutes for BioMedical Research, Basel, Switzerland.
  • 3 Ridgeline Discovery, Basel, Switzerland.
  • 4 Novartis Institutes for BioMedical Research, Cambridge, MA, USA.
  • 5 Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
  • 6 Swiss Institute for Experimental Cancer Research (ISREC), École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
  • 7 Novartis Institutes for BioMedical Research, Cambridge, MA, USA. cthoma@ridgelinediscovery.com.
  • 8 Ridgeline Discovery, Basel, Switzerland. cthoma@ridgelinediscovery.com.
  • # Contributed equally.
PMID: 38177131 DOI: 10.1038/s41467-023-44237-4
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.

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