研究人员介绍了一种被称为decryptM的蛋白质组学检测方法，对细胞中成千上万的变翻译后修饰（PTM）进行量化，以阐明目标参与和药物作用机制（MoA）。包括检测化疗药物的DNA损伤在内的例子确定了激酶抑制剂的药物特异性PTM特征，以及证明了利妥昔单抗通过过度激活B细胞受体信号传导杀死CD20阳性B细胞。在13个细胞系中对31种癌症药物进行DecryptM分析，研究人员证明了该方法的广泛适用性。由此产生的180万条剂量反应曲线被作为ProteomicsDB的互动分子资源提供。
据了解，尽管大多数抗癌药物通过改变PTM来调节细胞通路的活性，但令人惊讶的是，人们对药物调节PTM的程度以及时间和剂量反应特征知之甚少。
附：英文原文
Title: Decrypting drug actions and protein modifications by dose- and time-resolved proteomics
Author: Jana Zecha, Florian P. Bayer, Svenja Wiechmann, Julia Woortman, Nicola Berner, Julian Müller, Annika Schneider, Karl Kramer, Mar Abril-Gil, Thomas Hopf, Leonie Reichart, Lin Chen, Fynn M. Hansen, Severin Lechner, Patroklos Samaras, Stephan Eckert, Ludwig Lautenbacher, Maria Reinecke, Firas Hamood, Polina Prokofeva, Larsen Vornholz, Chiara Falcomatà, Madeleine Dorsch, Ayla Schrder, Anton Venhuizen, Stephanie Wilhelm, Guillaume Médard, Gabriele Stoehr, Jürgen Ruland, Barbara M. Grüner, Dieter Saur, Maike Buchner, Benjamin Ruprecht, Hannes Hahne, Matthew The, Mathias Wilhelm, Bernhard Kuster
Issue&Volume: 2023-03-16
Abstract: 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.
DOI: ade3925
Source: https://www.science.org/doi/10.1126/science.ade3925