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


ABSTRACT: 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.

SUBMITTER: Zecha J 

PROVIDER: S-EPMC7615311 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature

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

Zecha Jana J   Bayer Florian P FP   Wiechmann Svenja S   Woortman Julia J   Berner Nicola N   Müller Julian J   Schneider Annika A   Kramer Karl K   Abril-Gil Mar M   Hopf Thomas T   Reichart Leonie L   Chen Lin L   Hansen Fynn M FM   Lechner Severin S   Samaras Patroklos P   Eckert Stephan S   Lautenbacher Ludwig L   Reinecke Maria M   Hamood Firas F   Prokofeva Polina P   Vornholz Larsen L   Falcomatà Chiara C   Dorsch Madeleine M   Schröder Ayla A   Venhuizen Anton A   Wilhelm Stephanie S   Médard Guillaume G   Stoehr Gabriele G   Ruland Jürgen J   Grüner Barbara M BM   Saur Dieter D   Buchner Maike M   Ruprecht Benjamin B   Hahne Hannes H   The Matthew M   Wilhelm Mathias M   Kuster Bernhard B  

Science (New York, N.Y.) 20230316 6640


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 identify  ...[more]

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