Development of STAT3 dimerization inhibitors for cancers
The constant activation of Signal Transducer and Activator of Transcription 3 (STAT3) is frequently detected in many cancer patients with advanced diseases. About 80% of all cancers overexpress STAT3, including solid tumors, lymphoma, and leukemia. Constant activation of STAT3 activities in nonmalignant human prostatic epithelial cells can induce tumor formation of these cells in mice, suggesting that activated STAT3 can promote prostate cancer progression. Activated STAT3 stimulates cancer cell growth, promotes angiogenesis, and promotes resistance to cell death induced by chemotherapy. Because STAT3 is frequently activated in many cancers and contributes to cancer progression and survival, there is a need to develop inhibitors that block STAT3 function.
Researchers at The Ohio State University, led by Dr. Pui-Kai Li, have developed the small molecule compound (LLL12) that is a selective inhibitor of STAT3 for the treatment of various cancers. Inhibiting activated STAT3 in cancer cells dramatically increased cell death, demonstrating that constant STAT3 signaling is crucial for the survival and growth of tumor cells. It also shows that STAT3 is a highly important and true therapeutic target for cancer, since once it is inhibited, cancer cells die quickly. LLL12 inhibits downstream target genes and signaling pathways. In vivo, the drug reduces tumor growth in murine cancer models. It is also better able to permeate cells and retains stability. LLL12 could be a viable clinical option for chemotherapeutic treatments.
- Short synthetic route
- High selectivity for STAT3
- Greater potency
- Possibility for combination therapy