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

Overview

Journal ACS Chem Biol

Publisher American Chemical Society

Specialties Biochemistry
Biology

Date 2022 Jul 6

PMID 35793809

Authors

Maria-Anna Trapotsi

Elizabeth Mouchet

Guy Williams

Tiziana Monteverde

Karolina Juhani

Riku Turkki

Filip Miljkovic

Anton Martinsson

Lewis Mervin

Kenneth R Pryde

Erik Mullers

Ian Barrett

Ola Engkvist

Andreas Bender

Kevin Moreau

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

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