The Research Center of Chiral Drugs, Innovation Research Institute of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, 3663N Zhongshan Road, Shanghai 200062, China.
Bioorg Med Chem. 2020 Dec 15;28(24):115822. doi: 10.1016/j.bmc.2020.115822. Epub 2020 Oct 22.
Signal transducer and activator of transcription 3 (STAT3) is identified as a promising target for multiple cancer therapy and attracts widespread concern. Herein, we reported the discovery of a series of 2-acetyl-7-phenylamino benzofuran derivatives as STAT3 inhibitors using scaffold fusion strategy. Further structure activity relationship study led to the discovery of compound C6, which displayed the most potent anti-proliferation activities against MDA-MB-468 cells (IC = 0.16 μM). Western blot assay demonstrated that C6 inhibited the activation of STAT3 (Tyr705) without influencing the phosphorylation of STAT1 (Tyr701). Further mechanistic studies indicated that C6 caused a notable G2/M cycle-arresting and early apoptosis in a concentration-dependent manner in MDA-MB-468 cells. Finally, molecular modelling study elucidated the binding mode of C6 in STAT3 SH2 domain.
信号转导子和转录激活子 3（STAT3）被确定为多种癌症治疗的有前途的靶点，引起了广泛关注。在此，我们报道了使用支架融合策略发现的一系列 2-乙酰-7-苯基氨基苯并呋喃衍生物作为 STAT3 抑制剂。进一步的构效关系研究导致发现了化合物 C6，其对 MDA-MB-468 细胞表现出最强的抗增殖活性（IC = 0.16 μM）。Western blot 分析表明 C6 抑制了 STAT3（Tyr705）的激活，而不影响 STAT1（Tyr701）的磷酸化。进一步的机制研究表明，C6 以浓度依赖性方式在 MDA-MB-468 细胞中引起明显的 G2/M 周期阻滞和早期凋亡。最后，分子建模研究阐明了 C6 在 STAT3 SH2 结构域中的结合模式。
