On the Scope of DCAF1-Recruiting PROTACs Degrading Protein Kinases
Proteolysis-targeting chimeras (PROTACs) have emerged as a novel drug modality, but their development currently relies on a limited number of E3 ligase ligands, primarily targeting CRBN and VHL. Conversely, current validation studies on novel E3 ligase ligands are typically limited to a few highly degradable targets, like BRD4. Here, we used our previously established workflow for E3 ligase ligand validation, employing promiscuous kinase PROTACs, to evaluate the potential of recruiting DCAF1 for PROTAC development. Our study revealed the DCAF1-dependent degradation of a diverse set of kinases, which were validated in orthogonal assays. In a comparative analysis, we identified a significant overlap between the degradable kinome of DCAF1- versus CRBN-recruiting PROTACs, suggesting alternative design strategies for PROTACs using available structurally diverse DCAF1 ligands. Moreover, ubiquitinomics analysis of the PROTAC-induced ubiquitination patterns provided insight into substrate- and isoform-selective degradation. The presented data will establish DCAF1-recruiting PROTACs as a versatile design strategy for future degrader development.
Authors
- T J Dietz
- Ingo V. Hartung (ORCID: https://orcid.org/0000-0001-8750-679X)
- Bikash Adhikari (ORCID: https://orcid.org/0000-0002-9064-0356)
- Martin Steger (ORCID: https://orcid.org/0000-0003-1637-8190)
- Stefan Knapp (ORCID: https://orcid.org/0000-0001-5995-6494)
- Bachuki Shashikadze (ORCID: https://orcid.org/0000-0003-4558-0785)
- Václav Němec (ORCID: https://orcid.org/0000-0001-6900-1368)
- A Wegener
- Martin P. Schwalm (ORCID: https://orcid.org/0000-0002-1252-1829)
- Janik Weckesser (ORCID: https://orcid.org/0000-0001-5100-2776)
- Henrik Daub
- Susanne Müller (ORCID: https://orcid.org/0000-0003-2402-4157)
- Uli Ohmayer (ORCID: https://orcid.org/0000-0003-0438-0410)
- Lewis Elson (ORCID: https://orcid.org/0009-0004-6142-3653)
- Andrea Unzue Lopez
- Elmar Wolf (ORCID: https://orcid.org/0000-0002-5299-6335)
- Andreas Krämer (ORCID: https://orcid.org/0000-0003-3294-2660)
- Saran Aswathaman Sivashanmugam
- Nebojša Miletić
- Tobias Hammann
- Paul Gehrtz
Institutions
- Goethe University Frankfurt (DE)
- Merck KGaA, Darmstadt (Germany) (DE)
- German Cancer Research Center (DE)
- Christian-Albrechts-Universität zu Kiel (DE)
- German Centre for Cardiovascular Research (DE)
- Georg Speyer Haus (DE)
- Frankfurt Cancer Institute (DE)
- John Deere (Germany) (DE)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2026-06-17
- DOI
- https://doi.org/10.1021/acs.jmedchem.6c00383
- Primary Topic
- Protein Degradation and Inhibitors
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Deutschen Konsortium für Translationale Krebsforschung