Twenty-five years of laboratory research have provided compelling genetic and functional data establishing STAT3 (signal transducer and activator of transcription 3) as a critical node in cancer, inflammation and fibrosis. Bharadwaj et al, STAT Inhibitors in Cancer, 2016. Tvardi Therapeutics was established in 2017 to advance its lead compound, TTI-101, which is a small-molecule inhibitor of STAT3. In addition to TTI-101, Tvardi is developing other inhibitors as a potential treatment for cancer and other diseases.
These inhibitors bind tightly to STAT3 and block STAT3 recruitment to signaling complexes that contain activated tyrosine kinases, thereby preventing STAT3 phosphorylation on Y705 and STAT3 activation. Xu et al, PLoS One, 2009. Binding to STAT3 also prevents STAT3 homo-dimerization (see image).
STAT3 drives the development of cancer, inflammatory diseases and fibrosis. Collectively, the societal and economic impact of STAT3-dependent disease is significant. With over 50 million people afflicted annually in the USA alone, Tvardi is highly motivated to develop safe and effective small molecule inhibitors of STAT3 for use across these diseases.
STAT3 is activated in greater than 50% of all cancers and gain-of-function mutations are present in leukemia and lymphoma. In mouse models, the genetic deletion of STAT3 blocks the development of cancer, suggesting that a STAT3 inhibitor may represent a novel and effective treatment for diverse cancer types. In addition, STAT3 plays a central role in enabling cancer cells to become resistant to chemotherapy or radiation and STAT3 inhibition can re-sensitize these resistant cancers to standard therapies. Finally, and importantly, STAT3 is a major mediator of mechanisms governing tumor immune evasion, anticipating that an inhibitor of STAT3 could work synergistically with immune therapies such as immune checkpoint blockade therapy.
STAT3 plays an integral role in activating immune mechanisms driving inflammation including those central to inflammatory bowel disease, asthma, anaphylaxis, and cachexia. Hox et al, J Allergy Clinical Immunology, 2016. On the genetic level, loss-of-function mutations in STAT3 impair pro-inflammatory T cell generation in humans and, importantly, STAT3 deficiency is otherwise well-tolerated in humans suggesting minimal on-target side effects from an inhibitor of STAT3. In mouse models of the aforementioned inflammatory diseases, an inhibitor of STAT3 shows significant amelioration of the signs and symptoms of disease.
STAT3 plays an essential role in fibrogenesis. Strikingly, the loss of only one STAT3 gene protects mice from bleomycin-induced lung fibrosis (a model of idiopathic pulmonary fibrosis) and skin fibrosis (a model of scleroderma). Notably, STAT3 deletion in mice blocks the capacity of mice to develop liver cirrhosis which is the seventh leading cause of death by disease worldwide.