A low-molecular-weight compound discovered through virtual database screening inhibits Stat3 function in breast...

This study focused on the screening of small-molecule inhibitors that target signal transducers and activators of transcription 3 (Stat3) in human breast carcinoma. The constitutive activation of Stat3 is frequently detected in human breast cancer cell lines as well as clinical breast cancer specimens and may play an important role in the oncogenesis of breast carcinoma. Activated Stat3 may participate in oncogenesis by stimulating cell proliferation, promoting tumor angiogenesis, and resisting apoptosis. Because a variety of human cancers are associated with constitutively active Stat3, Stat3 represents an attractive target for cancer therapy. In this study, of the nearly 429,000 compounds screened by virtual database screening, chemical samples of top 100 compounds identified as candidate small-molecule inhibitors of Stat3 were evaluated by using Stat3-dependent luciferase reporter as well as other cell-based assays. Through serial functional evaluation based on our established cell-based assays, one compound, termed STA-21, was identified as the best match for our selection criteria. Further investigation demonstrated that STA-21 inhibits Stat3 DNA binding activity, Stat3 dimerization, and Stat3-dependent luciferase activity. Moreover, STA-21 reduces the survival of breast carcinoma cells with constitutive Stat3 signaling but has minimal effect on the cells in which constitutive Stat3 signaling is absent. Together, these results demonstrate that STA-21 inhibits breast cancer cells that express constitutively active Stat3.