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

Trapotsi, Maria-Anna Mouchet, Elizabeth Williams, Guy Monteverde, Tiziana Juhani, Karolina Turkki, Riku Miljkovic, Filip Martinsson, Anton Mervin, Lewis Pryde, Kenneth R. Mullers, Erik Barrett, Ian Engkvist, Ola Bender, Andreas Moreau, Kevin

ACS Chemical Biology2022，Vol.17Issue(7) ：12.DOI:10.1021/acschembio.2c000761733

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NSTL
Amer Chemical Soc

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

Trapotsi, Maria-Anna ¹Mouchet, Elizabeth ¹Williams, Guy ¹Monteverde, Tiziana ¹Juhani, Karolina ¹Turkki, Riku ¹Miljkovic, Filip ¹Martinsson, Anton ¹Mervin, Lewis ¹Pryde, Kenneth R. ¹Mullers, Erik ¹Barrett, Ian ¹Engkvist, Ola ¹Bender, Andreas ¹Moreau, Kevin¹

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作者信息

1. AstraZeneca
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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.

Key words

AMP Exception/MITOCHONDRIAL TOXICITY/PREDICTION/MECHANISM/ASSAY

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出版年

2022

ACS Chemical Biology

SCI

ISSN：1554-8929

被引量8

参考文献量38

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