Cell Morphological Profiling Enables High-Throughput Screening for PROteolysis TArgeting Chimera (PROTAC) Phenotypic Signature

PROteolysis TArgeting Chimeras (PROTACs) use the ubiquitin-proteasome system to degrade a protein of interest for therapeutic benefit. Advances made in targeted protein degradation technology have been remarkable, with several molecules having moved into clinical studies. However, robust routes to assess and better understand the safety risks of PROTACs need to be identified, which is an essential step toward delivering efficacious and safe compounds to patients. In this work, we used Cell Painting, an unbiased high-content imaging method, to identify phenotypic signatures of PROTACs. Chemical clustering and model prediction allowed the identification of a mitotoxicity signature that could not be expected by screening the individual PROTAC components. The data highlighted the benefit of unbiased phenotypic methods for identifying toxic signatures and the potential to impact drug design.

Automated summary

This study used unbiased high-content imaging method Cell Painting to identify phenotypic signatures of PROTACs and discovered mitochondrial toxicity signatures that could not be expected by screening individual PROTAC components. The results highlight the potential of unbiased phenotypic methods in identifying toxic signatures and impacting drug design.