University of Chinese Academy of Sciences, NO.19A Yuquan Road, Beijing 100049, P. R. China.
Department of Analytical Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica Chinese Academy of Sciences, Shanghai 201203, China.
J Med Chem. 2024 Mar 28;67(6):4804-4818. doi: 10.1021/acs.jmedchem.3c02371. Epub 2024 Mar 11.
Proteolysis-targeting chimera (PROTAC) is a powerful technology that can effectively trigger the degradation of target proteins. The intricate interplay among various factors leads to a heterogeneous drug response, bringing about significant challenges in comprehending drug mechanisms. Our study applied data-independent acquisition-based mass spectrometry to multidimensional proteome profiling of PROTAC (DIA-MPP) to uncover the efficacy and sensitivity of the PROTAC compound. We profiled the signal transducer and activator of transcription 3 (STAT3) PROTAC degrader in six leukemia and lymphoma cell lines under multiple conditions, demonstrating the pharmacodynamic properties and downstream biological responses. Through comparison between sensitive and insensitive cell lines, we revealed that STAT1 can be regarded as a biomarker for STAT3 PROTAC degrader, which was validated in cells, patient-derived organoids, and mouse models. These results set an example for a comprehensive description of the multidimensional PROTAC pharmacodynamic response and PROTAC drug sensitivity biomarker exploration.
蛋白水解靶向嵌合体（PROTAC）是一种强大的技术，可以有效地触发靶蛋白的降解。各种因素之间的复杂相互作用导致药物反应的异质性，从而在理解药物机制方面带来重大挑战。我们的研究应用基于数据非依赖性采集的质谱技术进行多维蛋白质组学分析（DIA-MPP），以揭示 PROTAC 化合物的疗效和敏感性。我们在多种条件下对六种白血病和淋巴瘤细胞系中的信号转导子和转录激活子 3（STAT3）PROTAC 降解剂进行了分析，展示了其药效学特性和下游生物学反应。通过对敏感和不敏感细胞系的比较，我们揭示了 STAT1 可以作为 STAT3 PROTAC 降解剂的生物标志物，这在细胞、患者来源的类器官和小鼠模型中得到了验证。这些结果为全面描述多维 PROTAC 药效反应和 PROTAC 药物敏感性生物标志物探索提供了范例。
