Discovery of a novel STAT3 inhibitor: A potential application for pancreatic cancer treatment

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is projected to become the second leading cause of cancer-related deaths by 2030, with most patients presenting with advanced, unresectable disease. Despite advances in chemotherapy, the 5-year survival rate remains low, underscoring the need for novel therapies. This study builds on the discovery that palmatine, a natural compound inhibits pancreatic cancer growth and enhances gemcitabine efficacy. This was done by using computational docking to explore palmatine's interaction with the STAT3 linker domain. A screening of 139,735 compounds from the National Cancer Institute Developmental Therapeutics Program identified compounds with superior STAT3 binding, with Striatal B emerging as the lead. In vitro tests confirmed the ability of Striatal B to significantly inhibit pancreatic cancer cell growth and potentiate gemcitabine effects, while computational modeling indicated effective binding to STAT3. Striatal B reduced STAT3 activation and epithelial-mesenchymal transition markers and modulated mechanical properties, suggesting a mechanism of action that involves altering cell mechanics, potentially providing a promising new therapeutic avenue for PDAC treatment.