Chemical Biology, Merck, Boston, MA, USA.
Chemoinformatics, Merck, Boston, MA, USA.
Nat Chem Biol. 2020 Oct;16(10):1111-1119. doi: 10.1038/s41589-020-0572-3. Epub 2020 Jul 20.
Mass spectrometry-based discovery proteomics is an essential tool for the proximal readout of cellular drug action. Here, we apply a robust proteomic workflow to rapidly profile the proteomes of five lung cancer cell lines in response to more than 50 drugs. Integration of millions of quantitative protein-drug associations substantially improved the mechanism of action (MoA) deconvolution of single compounds. For example, MoA specificity increased after removal of proteins that frequently responded to drugs and the aggregation of proteome changes across cell lines resolved compound effects on proteostasis. We leveraged these findings to demonstrate efficient target identification of chemical protein degraders. Aggregating drug response across cell lines also revealed that one-quarter of compounds modulated the abundance of one of their known protein targets. Finally, the proteomic data led us to discover that inhibition of mitochondrial function is an off-target mechanism of the MAP2K1/2 inhibitor PD184352 and that the ALK inhibitor ceritinib modulates autophagy.
基于质谱的发现蛋白质组学是细胞药物作用近程读出的重要工具。在这里，我们应用稳健的蛋白质组学工作流程来快速分析五种肺癌细胞系对 50 多种药物的反应的蛋白质组。将数百万个定量蛋白质-药物关联进行整合，大大提高了单一化合物作用机制（MoA）分解的能力。例如，在去除经常对药物产生反应的蛋白质后，MoA 的特异性增加，而跨细胞系聚集的蛋白质组变化则解决了化合物对蛋白质稳定性的影响。我们利用这些发现来证明化学蛋白降解剂的有效靶标鉴定。跨细胞系的药物反应聚集还表明，四分之一的化合物调节了其已知蛋白质靶标的丰度。最后，蛋白质组学数据使我们发现，抑制线粒体功能是 MAP2K1/2 抑制剂 PD184352 的一种非靶标机制，而 ALK 抑制剂色瑞替尼调节自噬。
