Discovery, Optimization, and Evaluation of Novel N -(Benzimidazol-5-yl)-1,3,4-thiadiazol-2-amine Analogues as Potent STAT3 Inhibitors for Cancer Treatment

作者：Ru Wang, Tingting Du, Wenqiang Liu, Yichen Liu, Y. H. Yang, Jinping Hu, Ming Ji, Beibei Yang, Li Li, Xiaoguang Chen · 发表于：Journal of Medicinal Chemistry · 年份：2023 · DOI：10.1021/acs.jmedchem.3c00863 · 被引用次数：18 · 研究领域：Cytokine Signaling Pathways and Interactions、Quinazolinone synthesis and applications、Synthesis and biological activity

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 (IC 50 value = 2.97 μM) and MDA-MB-231 (IC 50 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.