Constitutive activation of the signal transducers and activators of transcription 3 (Stat3) is frequently detected in breast cancer specimens from patients with advanced diseases and breast cancer cell lines, but not in normal breast epithelial cells. Persistent activation of Stat3 may not only provide a growth advantage for cancer cells, but also confer resistance to conventional therapies. Stat3 protein thus represents a highly promising molecular target for designing an entirely new class of anticancer drugs for breast cancer with potentially low toxicity to the normal cells.

Stat3 needs to form a homodimer in order to be activated. Therefore, blocking the dimerization of Stat3 using a drug-like, cell-permeable, non-peptide, small molecule may be an effective strategy to inhibit the activity of Stat3. To date, non-peptide, small molecule inhibitors of Stat3 have not been reported. In this Concept Award, we propose to discover such small molecule inhibitors through a computational structure-based database searching over 250,000 natural products and synthetic compounds to identify potential small molecules that can bind to the crucial Stat-3 dimerization site. We will test the most promising candidate molecules in appropriate binding and cellular assays to confirm their activity and specificity using human breast cancer cell lines with activated Stat3 and normal cells without activated Stat3. The success of this project will represent the first and a crucial step toward developing novel and potent small molecule inhibitors of Stat3 as potential new therapy for human breast cancer with constitutively active Stat3.