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Journal Article

Decrypting drug actions and protein modifications by dose- and time-resolved proteomics


Hansen,  Fynn M.
Mann, Matthias / Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Max Planck Society;

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Zecha, J., Bayer, F. P., Wiechmann, S., Woortman, J., Berner, N., Mueller, J., et al. (2023). Decrypting drug actions and protein modifications by dose- and time-resolved proteomics. Science, 380(6640). doi:10.1126/science.ade3925.

Cite as: https://hdl.handle.net/21.11116/0000-000D-3D12-B
Although most cancer drugs modulate the activities of cellular pathways by changing posttranslational modifications (PTMs), little is known regarding the extent and the time-and dose-response characteristics of drug-regulated PTMs. In this work, we introduce a proteomic assay called decryptM that quantifies drug-PTM modulation for thousands of PTMs in cells to shed light on target engagement and drug mechanism of action. Examples range from detecting DNA damage by chemotherapeutics, to identifying drug-specific PTM signatures of kinase inhibitors, to demonstrating that rituximab kills CD20-positive B cells by overactivating B cell receptor signaling. DecryptM profiling of 31 cancer drugs in 13 cell lines demonstrates the broad applicability of the approach. The resulting 1.8 million dose-response curves are provided as an interactive molecular resource in ProteomicsDB.