Beijing Key Laboratory of Active Substances Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050,China.
Beijing Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation Study, State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.
J Med Chem. 2023 Sep 14;66(17):12373-12395. doi: 10.1021/acs.jmedchem.3c00863. Epub 2023 Aug 18.
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 -(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 , compound was identified as a selective STAT3 inhibitor that directly binds the SH2 domain to inhibit STAT3 phosphorylation, translocation, and downstream gene transcription. Compound exhibited antiproliferative activities against STAT3-overactivated DU145 (IC value = 2.97 μM) and MDA-MB-231 (IC value = 3.26 μM) cancer cells and induced cell cycle arrest and apoptosis. In the DU145 xenograft model, compound 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.
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，要找到具有药物样特性的强效和选择性 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 -(苯并咪唑-5-基)-1,3,4-噻二唑-2-胺支架的化合物，并在 HEK-Blue IL-6 报告细胞中测试了它们对白细胞介素-6（IL-6）/JAK/STAT3 通路的抑制作用。在对先导化合物进行优化后，确定化合物 为选择性 STAT3 抑制剂，它直接结合 SH2 结构域抑制 STAT3 磷酸化、易位和下游基因转录。化合物 对 STAT3 过激活的 DU145（IC 值=2.97 μM）和 MDA-MB-231（IC 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细胞凋亡。在 DU145 异种移植模型中，化合物 经腹腔给药后显示出体内抗肿瘤疗效，在 50mg/kg 时肿瘤生长抑制率为 65.3%，表明具有进一步开发的潜力。
