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Cell morphological profiling enables high-throughput screening for PROteolysis TArgeting Chimera (PROTAC) phenotypic signature

Maria-Anna Trapotsi, Elizabeth Mouchet, Guy Williams, Tiziana Monteverde, Karolina Juhani, Riku Turkki, Filip Miljković, Anton Martinsson, Lewis Mervin, Erik Müllers, Ian Barrett, Ola Engkvist, Andreas Bender, Kevin Moreau
doi: https://doi.org/10.1101/2022.01.17.476610
Maria-Anna Trapotsi
1Department of Chemistry, Centre for Molecular Informatics, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK
7Data Sciences & Quantitative Biology, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK
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Elizabeth Mouchet
2High Throughput Screening, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Macclesfield, UK
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Guy Williams
2High Throughput Screening, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Macclesfield, UK
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Tiziana Monteverde
2High Throughput Screening, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Macclesfield, UK
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Karolina Juhani
2High Throughput Screening, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Macclesfield, UK
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Riku Turkki
3Data Sciences & Quantitative Biology, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
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Filip Miljković
4Imaging and Data Analytics, Clinical Pharmacology & Safety Sciences R&D, AstraZeneca, Gothenburg SE-43183, Sweden
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Anton Martinsson
4Imaging and Data Analytics, Clinical Pharmacology & Safety Sciences R&D, AstraZeneca, Gothenburg SE-43183, Sweden
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Lewis Mervin
5Molecular AI, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK
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Erik Müllers
6Bioscience Cardiovascular, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
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Ian Barrett
7Data Sciences & Quantitative Biology, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK
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Ola Engkvist
8Molecular AI, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
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Andreas Bender
1Department of Chemistry, Centre for Molecular Informatics, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK
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Kevin Moreau
9Safety Innovation, Clinical Pharmacology and Safety Sciences R&D, AstraZeneca, Cambridge, UK
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  • For correspondence: kevin.moreau@astrazeneca.com
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Summary

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.

Highlights

  • Morphological profiling detects various PROTACs’ phenotypic signatures

  • Phenotypic signatures can be attributed to diverse biological responses

  • Chemical clustering from phenotypic signatures separates on drug selection

  • Trained in-silico machine learning models to predict PROTACs’ mitochondrial toxicity

Competing Interest Statement

All authors except of Maria-Anna Trapotsi and Andreas Bender are AstraZeneca employees

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted January 18, 2022.
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Cell morphological profiling enables high-throughput screening for PROteolysis TArgeting Chimera (PROTAC) phenotypic signature
Maria-Anna Trapotsi, Elizabeth Mouchet, Guy Williams, Tiziana Monteverde, Karolina Juhani, Riku Turkki, Filip Miljković, Anton Martinsson, Lewis Mervin, Erik Müllers, Ian Barrett, Ola Engkvist, Andreas Bender, Kevin Moreau
bioRxiv 2022.01.17.476610; doi: https://doi.org/10.1101/2022.01.17.476610
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Cell morphological profiling enables high-throughput screening for PROteolysis TArgeting Chimera (PROTAC) phenotypic signature
Maria-Anna Trapotsi, Elizabeth Mouchet, Guy Williams, Tiziana Monteverde, Karolina Juhani, Riku Turkki, Filip Miljković, Anton Martinsson, Lewis Mervin, Erik Müllers, Ian Barrett, Ola Engkvist, Andreas Bender, Kevin Moreau
bioRxiv 2022.01.17.476610; doi: https://doi.org/10.1101/2022.01.17.476610

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