Proteome‐Wide Profiling of Olaparib Interactors Using a Biotinylated Photoaffinity Probe
ChemBioChem, vol. 26, pp. e202400882
Abstract
Olaparib is a widely used PARP inhibitor for the treatment of BRCA-mutated cancers. To comprehensively understand the drug's clinical impact, measuring its interactions with intended on- and off-targets is crucial. In this study, olaparib's on- and off-targets were profiled using photoaffinity labeling, a powerful, proteome-wide method for studying the direct interactions between a drug and its protein targets. A novel photoaffinity probe was designed and used in a proteomic screening to discover novel targets of olaparib in the human proteome. The probe, incorporating a pre-installed biotin group, bypasses the limitations of using a copper(I)-catalyzed click reaction in cell lysates for reporter group conjugation and revealed a broad range of olaparib interactors, including previously unreported proteins, in a quantitative mass spectrometry-based proteomic screening using HeLa whole cell lysate. This study contributes to our current understanding of the pharmacology of olaparib and provides a valuable tool for elucidating drug interactors within cell lysates, potentially guiding the development of more targeted therapeutics with fewer off-targets.
Authors 6
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Affiliation as printed
Leiden Institute of Chemistry Leiden University Einsteinweg 55, 2333 CC Leiden The Netherlands
Leiden University: Universiteit Leiden, Leiden Institute of Chemistry, NETHERLANDS, KINGDOM OF THE
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Radboud University Nijmegen · Radboud Institute for Molecular Life Sciences · The Netherlands Cancer Institute
Affiliation as printed
Department of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Oncode Institute Radboud University Geert Grooteplein 28, 6525 GA Nijmegen The Netherlands
Division of Molecular Genetics The Netherlands Cancer Institute Plesmanlaan 121, 1066 CX Amsterdam The Netherlands
The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital: Antoni van Leeuwenhoek, Division of Molecular Genetics, NETHERLANDS, KINGDOM OF THE
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The Netherlands Cancer Institute
Affiliation as printed
Division of Molecular Genetics The Netherlands Cancer Institute Plesmanlaan 121, 1066 CX Amsterdam The Netherlands
The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital: Antoni van Leeuwenhoek, Division of Molecular Genetics, NETHERLANDS, KINGDOM OF THE
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Radboud University Nijmegen · Radboud Institute for Molecular Life Sciences · Max Planck Institute of Molecular Physiology
Affiliation as printed
Department of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Oncode Institute Radboud University Geert Grooteplein 28, 6525 GA Nijmegen The Netherlands
Max Planck Institute of Molecular Physiology Otto-Hahn Strasse 11, 44227 Dortmund Germany
Radboud University Nijmegen Radboud Institute for Molecular Life Sciences: Radboud Universiteit Radboud Institute for Molecular Life Sciences, Department of Molecular Biology, NETHERLANDS, KINGDOM OF THE
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Michiel Vermeulen corresponding
Radboud University Nijmegen · Radboud Institute for Molecular Life Sciences · The Netherlands Cancer Institute
Affiliation as printed
Department of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Oncode Institute Radboud University Geert Grooteplein 28, 6525 GA Nijmegen The Netherlands
Division of Molecular Genetics The Netherlands Cancer Institute Plesmanlaan 121, 1066 CX Amsterdam The Netherlands
The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital: Antoni van Leeuwenhoek, Division of Molecular Genetics, NETHERLANDS, KINGDOM OF THE
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Affiliation as printed
Leiden Institute of Chemistry Leiden University Einsteinweg 55, 2333 CC Leiden The Netherlands
Leiden Institute of Chemstry, Bio-organic Synthesis, Einsteinweg 55, 2333 CC Leiden Leiden, NETHERLANDS, KINGDOM OF THE
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