Abstract：
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.
摘要：
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。各种因素之间复杂的相互作用导致异质的药物反应，在理解药物机制方面带来重大挑战。我们的研究将数据无关的基于采集的质谱应用于PROTAC（DIA-MPP）的多维蛋白质组分析，以揭示PROTAC化合物的功效和灵敏度。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和转录激活因子3（STAT3）PROTAC降解物进行了分析，展示药效学特性和下游生物反应。通过敏感和不敏感细胞系之间的比较，我们发现STAT1可以被视为STAT3PROTAC降解剂的生物标志物，这在细胞中得到了验证，患者来源的类器官，和老鼠模型。这些结果为多维PROTAC药效学反应和PROTAC药物敏感性生物标志物探索的全面描述树立了榜样。
