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 Thomas, Damien Begue, Maryam Khoshouei, Peggy Lefeuvre, Rita Andraos-Rey, BoYee Chung, Renate Ma, Benika Pinch, Andreas Hofmann, Markus Schirle, Niko Schmiedeberg, Patricia Imbach, Delphine Gorses, Keith Calkins, Beatrice Bauer-Probst, Magdalena Maschlej, Matt Niederst, Rob Maher, Martin Henault, John Alford, Erik Ahrne, Luca Tordella, Greg Hollingworth, Nicolas H Thomä, Anna Vulpetti, Thomas Radimerski, Philipp Holzer, Seth Carbonneau, Claudio R Thoma
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...
January 4, 2024: Nature Communications