Structure-Based Discovery and Testing of Non-Peptide, Cell-Permeable Small Molecule Inhibitors of STAT-3 as a Potential Novel Therapy for Breast Cancer

摘要

The constitutive activation of Stat3 is frequently detected in human breast cancer cell lines as well as in clinical breast cancer specimens and may play an important role in oncogenesis of breast carcinoma. Activated Stat3 may participate in oncogenesis by stimulating cell proliferation, promoting tumor angiogenesis, and resisting to apoptosis. Hence, 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 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 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 constitutive active Stat3. Sta-21 may have a therapeutic potential to be developed as a new class of anti-cancer drug for the treatment of human cancer with activated Stat3.