Signal transducer and activator of transcription 3 (STAT3) is an attractive target for cancer therapy. However, identifying potent and selective STAT3 small-molecule inhibitors with drug-like properties remains challenging. Based on a scaffold combination strategy, compounds with a novel N-(benzimidazol-5-yl)-1,3,4-thiadiazol-2-amine scaffold were designed and their inhibition of the interleukin-6 (IL-6)/JAK/STAT3 pathway was tested in HEK-Blue IL-6 reporter cells. After optimization of lead compound 12, compound 40 was identified as a selective STAT3 inhibitor that directly binds the SH2 domain to inhibit STAT3 phosphorylation, translocation, and downstream gene transcription. Compound 40 exhibited antiproliferative activities against STAT3-overactivated DU145 (IC₅₀ value = 2.97 μM) and MDA-MB-231 (IC₅₀ value = 3.26 μM) cancer cells and induced cell cycle arrest and apoptosis. In the DU145 xenograft model, compound 40 showed in vivo antitumor efficacy following intraperitoneal administration, with a tumor growth inhibition rate of 65.3% at 50 mg/kg, indicating promise for further development.

中文翻译：

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新型 N-(苯并咪唑-5-基)-1,3,4-噻二唑-2-胺类似物作为有效 STAT3 抑制剂用于癌症治疗的发现、优化和评估

信号转导子和转录激活子 3 (STAT3) 是癌症治疗的一个有吸引力的靶点。然而，鉴定具有药物样特性的有效且选择性的 STAT3 小分子抑制剂仍然具有挑战性。基于支架组合策略，设计了具有新型N- (苯并咪唑-5-基)-1,3,4-噻二唑-2-胺支架的化合物，及其对白细胞介素6 (IL-6)/JAK的抑制作用/STAT3 通路在 HEK-Blue IL-6 报告细胞中进行了测试。对先导化合物12进行优化后，化合物40被鉴定为选择性 STAT3 抑制剂，可直接结合 SH2 结构域，抑制 STAT3 磷酸化、易位和下游基因转录。化合物40对STAT3过度激活的DU145（IC ₅₀值= 2.97 μM）和MDA-MB-231（IC ₅₀值= 3.26 μM）癌细胞表现出抗增殖活性，并诱导细胞周期停滞和凋亡。在DU145异种移植模型中，腹腔给药后化合物40显示出体内抗肿瘤功效，50 mg/kg时肿瘤生长抑制率为65.3%，表明有进一步开发的前景。