Year: 2026
Type: article
Abstract: 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.
Source: Journal of Medicinal Chemistry
Authors: Janik Weckesser, Nebojša Miletić, Saran Aswathaman Sivashanmugam, Uli Ohmayer, Martin Steger, Bachuki Shashikadze, Paul Gehrtz, Andrea Unzue Lopez, Ansgar Wegener, Timo Yoshua Dietz, Tobias Hammann, Ingo V. Hartung, Lewis Elson, Václav Němec, Martin Peter Schwalm, Bikash Adhikari, Elmar Wolf, Andreas Krämer, Susanne Müller, Henrik Daub, Stefan Knapp
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $4,500
OpenAlex ID: W7165048934