Wang Kefeng, Zheng Yuxin, Mao Wenli, Xu Jing, Wang Yukun
Department of Pharmacology, School of Medicine, Southern University of Science and Technology Shenzhen 518055 China
Department of Chemistry and Shenzhen Grubbs Institute and Guangdong Provincial Key Laboratory of Catalysis and Shenzhen Key Laboratory of Small Molecule Drug Discovery and Synthesis, Southern University of Science and Technology Shenzhen 518055 China
RSC Med Chem. 2025 Jul 31. doi: 10.1039/d5md00260e.
The signal transducer and activator of transcription 3 (STAT3) protein and the p53 protein play opposite roles in the regulation of cell pathways. Activation of STAT3 upregulates survival pathways, while activation of p53 triggers apoptosis pathways. Therefore, STAT3 inhibition of p53 expression may play a central role in tumor development, and targeting STAT3 represents a promising therapeutic method for p53 reactivation in many cancers. Here, we report the design of S3D5, a BP-1-102-based proteolysis targeting chimera (PROTAC) that induces time- and dose-dependent degradation of STAT3 in HepG2 cells without significant effects on other STAT proteins. Preliminary mechanism studies show that S3D5 degradation of the STAT3 protein is mediated by the ubiquitin-proteasome system (UPS). S3D5 exhibits good anti-hepatocellular carcinoma cell proliferation activity, which can be explained by activating the p53 pathway. These findings demonstrate the utility and importance of PROTACs as preliminary chemical tools to investigate the function of the STAT3 protein. Further, S3D5 may serve as a potential anti-hepatocellular carcinoma agent, laying a practical foundation for further development of potent STAT3-targeting PROTACs.
信号转导和转录激活因子3（STAT3）蛋白与p53蛋白在细胞信号通路调控中发挥相反作用。STAT3激活会上调生存信号通路，而p53激活则触发凋亡信号通路。因此，STAT3对p53表达的抑制可能在肿瘤发展中起核心作用，靶向STAT3代表了一种在多种癌症中重新激活p53的有前景的治疗方法。在此，我们报告了S3D5的设计，这是一种基于BP-1-102的蛋白酶靶向嵌合体（PROTAC），可在HepG2细胞中诱导STAT3的时间和剂量依赖性降解，而对其他STAT蛋白无显著影响。初步机制研究表明，S3D5介导的STAT3蛋白降解是由泛素-蛋白酶体系统（UPS）介导的。S3D5具有良好的抗肝癌细胞增殖活性，这可以通过激活p53信号通路来解释。这些发现证明了PROTAC作为研究STAT3蛋白功能的初步化学工具的实用性和重要性。此外，S3D5可能作为一种潜在的抗肝癌药物，为进一步开发强效的STAT3靶向PROTAC奠定了实践基础。
