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Although most cancer drugs modulate the activity of enzymes that regulate post-translational modifications (PTMs), little systematic information is available about drug action at the level of PTMs. To address this, Zecha et al. have developed a quantitative proteomic approach termed decryptM, which is able to assess target and pathway engagement and decrypt the mechanism of action of diverse cancer drugs by systematically measuring their dose- and time-resolved modulation of PTMs in cells. DecryptM was applied to 12 human cancer cell lines and 31 cancer drugs, comprising chemotherapeutic agents, protein interaction inhibitors, proteasome inhibitors, epigenetic drugs, kinase inhibitors and antibodies. Key findings from the decryptM analysis included the identification of novel phosphorylation sites linking chemotherapeutics to DNA damage response, new insight into how cells mount a stress response to covalent proteasome inhibitors, the characterization of drug-specific signatures for kinase inhibitors, and the discovery of a new model for the mode of action of the anti-CD20 antibody rituximab. The resulting 1.8 million drug dose–response curves are available as an interactive molecular resource in ProteomicsDB. The method should be applicable to any molecule that modulates cellular activity by affecting PTMs or protein expression.
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Nature Reviews Drug Discovery22, 355 (2023)
doi: https://doi.org/10.1038/d41573-023-00052-6
References
Zecha, J. et al. Decrypting drug actions and protein modifications by dose- and time-resolved proteomics. Sciencehttps://doi.org/10.1126/science.ade3925 (2023)