Proteomics is making important contributions to drug discovery, from target deconvolution to mechanism of action (MoA) elucidation and the identification of biomarkers of drug response. Here we introduce decryptE, a proteome-wide approach that measures the full dose–response characteristics of drug-induced protein expression changes that informs cellular drug MoA. Assaying 144 clinical drugs and research compounds against 8,000 proteins resulted in more than 1 million dose–response curves that can be interactively explored online in ProteomicsDB and a custom-built Shiny App. Analysis of the collective data provided molecular explanations for known phenotypic drug effects and uncovered new aspects of the MoA of human medicines. We found that histone deacetylase inhibitors potently and strongly down-regulated the T cell receptor complex resulting in impaired human T cell activation in vitro and ex vivo. This offers a rational explanation for the efficacy of histone deacetylase inhibitors in certain lymphomas and autoimmune diseases and explains their poor performance in treating solid tumors.

蛋白质组学为药物发现做出了重要贡献，从靶标解卷积到作用机制 (MoA) 阐明以及药物反应生物标志物的识别。在这里，我们介绍decryptE，一种全蛋白质组方法，可测量药物诱导的蛋白质表达变化的完整剂量反应特征，从而通知细胞药物MoA。针对 8,000 种蛋白质测定 144 种临床药物和研究化合物，得出了超过 100 万条剂量反应曲线，可以在 ProteomicsDB 和定制的 Shiny 应用程序中在线交互式探索。对集体数据的分析为已知的表型药物效应提供了分子解释，并揭示了人类药物 MoA 的新方面。我们发现组蛋白脱乙酰酶抑制剂有效且强烈地下调 T 细胞受体复合物，导致体外和离体的人类 T 细胞活化受损。这为组蛋白脱乙酰酶抑制剂在某些淋巴瘤和自身免疫性疾病中的功效提供了合理的解释，并解释了它们在治疗实体瘤方面表现不佳的原因。