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

Jana ZechaFlorian P BayerSvenja WiechmannJulia WoortmanNicola BernerJulian MüllerAnnika SchneiderKarl KramerMar Abril-GilThomas A HopfLeonie ReichartLin ChenFynn M HansenSeverin LechnerPatroklos SamarasStephan EckertLudwig LautenbacherMaria ReineckeFiras HamoodPolina ProkofevaLarsen VornholzChiara FalcomatàMadeleine DorschAyla SchröderAnton VenhuizenStephanie WilhelmGuillaume MédardGabriele StoehrJuergen RulandBarbara M GrünerDieter SaurMaike BuchnerBenjamin RuprechtHannes HahneMatthew TheMathias WilhelmBernhard Kuster
Published in: Science (New York, N.Y.) (2023)
Although most cancer drugs modulate the activities of cellular pathways by changing post-translational modifications (PTMs), surprisingly little is known regarding the extent and the time- and dose-response characteristics of drug-regulated PTMs. Here, we introduce a proteomic assay termed decryptM that quantifies drug-PTM modulation for thousands of PTMs in cells to shed light on target engagement and drug mechanism of action (MoA). 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 over-activating 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.
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