Abstract：
The signal transducer and activator of transcription 3 (STAT3) has been established as a crucial drug target in the development of antitumor agents. In this study, a series of 21 derivatives of the STAT3 inhibitor napabucasin were designed and synthesized. Through preliminary screening against tumor cell lines, SZ6 emerged as the most potent compound with half maximal inhibitory concentration (IC50) values of 46.3 nM, 66.4 nM, and 53.8 nM against HCT116, HepG2, and Hela cells respectively. Furthermore, SZ6 effectively suppressed tumor invasion and migration in HCT116 cell assays by inducing S-phase arrest and apoptosis through inhibition of Protein Kinase B (PKB/AKT) activity and induction of reactive oxygen species (ROS). The mechanism underlying SZ6\'s action involves inhibition of STAT3 phosphorylation, which was confirmed by western blotting analysis. Additionally, surface plasmon resonance (SPR) and cellular thermal shift assay (CETSA) demonstrated direct binding between SZ6 and STAT3. Notably, in vivo studies revealed that SZ6 significantly inhibited tumor growth without any observed organ toxicity. Collectively, these findings identify SZ6 as a promising STAT3 inhibitor for colorectal cancer treatment.
摘要：
信号转导和转录激活因子3（STAT3）已被确立为抗肿瘤药物开发中的关键药物靶标。在这项研究中,设计并合成了一系列STAT3抑制剂napabucasin的21种衍生物。通过对肿瘤细胞系的初步筛选，SZ6是最有效的化合物，半数最大抑制浓度（IC50）值为46.3nM，66.4nM,分别针对HCT116、HepG2和Hela细胞和53.8nM。此外，SZ6通过抑制蛋白激酶B（PKB/AKT）活性和诱导活性氧（ROS）来诱导S期停滞和凋亡，从而在HCT116细胞试验中有效抑制了肿瘤的侵袭和迁移。SZ6的作用机制涉及抑制STAT3磷酸化，通过蛋白质印迹分析证实了这一点。此外,表面等离子体共振（SPR）和细胞热移位测定（CETSA）证明了SZ6和STAT3之间的直接结合。值得注意的是,体内研究表明，SZ6显著抑制肿瘤生长，没有任何观察到的器官毒性。总的来说，这些发现确定SZ6是一种有前景的用于结直肠癌治疗的STAT3抑制剂.
