RT Journal Article
SR Electronic
T1 Cell morphological profiling enables high-throughput screening for PROteolysis TArgeting Chimera (PROTAC) phenotypic signature
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.01.17.476610
DO 10.1101/2022.01.17.476610
A1 Maria-Anna Trapotsi
A1 Elizabeth Mouchet
A1 Guy Williams
A1 Tiziana Monteverde
A1 Karolina Juhani
A1 Riku Turkki
A1 Filip Miljković
A1 Anton Martinsson
A1 Lewis Mervin
A1 Erik Müllers
A1 Ian Barrett
A1 Ola Engkvist
A1 Andreas Bender
A1 Kevin Moreau
YR 2022
UL http://biorxiv.org/content/early/2022/01/18/2022.01.17.476610.abstract
AB PROTACs (PROteolysis TArgeting Chimeras) use the ubiquitin-proteasome system to degrade a protein of interest for therapeutic benefit. Advances in targeted protein degradation technology have been remarkable with several molecules moving 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 towards 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.HighlightsMorphological profiling detects various PROTACs’ phenotypic signaturesPhenotypic signatures can be attributed to diverse biological responsesChemical clustering from phenotypic signatures separates on drug selectionTrained in-silico machine learning models to predict PROTACs’ mitochondrial toxicityCompeting Interest StatementAll authors except of Maria-Anna Trapotsi and Andreas Bender are AstraZeneca employees