STAT3 is an attractive therapeutic target for cancer therapy. However, due to low potency or poor druggability, none of its inhibitors are clinically available. Herein, a series of aminobenzo[b]thiophene 1, 1-dioxides with good drug-likeness properties were designed, synthesized and evaluated as STAT3 inhibitors. Most of them exhibited higher antitumor activity than the small-molecule STAT3 inhibitor, Stattic. Compound 15 was the most potent and had an IC₅₀ range in 0.33–0.75 μM in various cancer cell lines. The overexpressed and IL-6 induced phosphorylation levels of STAT3 were both inhibited by 15 without influencing the phosphorylation levels of the upstream kinases Src and Jak2. 15 also suppressed the expressions of STAT3 downstream gene, Bcl-2. 15 effectively increased the ROS levels of cancer cells, induced cancer cell apoptosis and abolished the colony formation ability of cancer cells without affecting bypass kinase p-Erk. Furthermore, 15 in vivo induced significant antitumor responses, and exhibited less toxicity than Doxorubicin. Together, this study described a class of new STAT3 inhibitors as antitumor agents.

STAT3是用于癌症治疗的有吸引力的治疗靶标。但是，由于效价低或可药物处理性差，因此没有任何一种抑制剂在临床上可用。在此，设计，合成并评价了一系列具有良好药物样性质的氨基苯并[ b ]噻吩1，1-二氧化物作为STAT3抑制剂。它们中的大多数显示出比小分子STAT3抑制剂Stattic更高的抗肿瘤活性。化合物15是最有效的化合物，在各种癌细胞系中的IC ₅₀范围在0.33–0.75μM之间。STAT3的过表达和IL-6诱导的磷酸化水平均被15抑制，而不会影响上游激酶Src和Jak2的磷酸化水平。15还抑制了STAT3下游基因Bcl-2的表达。15在不影响旁路激酶p-Erk的情况下有效提高了癌细胞的ROS水平，诱导了癌细胞的凋亡并取消了集落形成能力。此外，有15种 体内诱导显着的抗肿瘤反应，并且毒性比阿霉素低。总之，这项研究描述了一类新型STAT3抑制剂作为抗肿瘤药。