Discovery of a Highly Potent and Orally Bioavailable STAT3 Dual Phosphorylation Inhibitor for Pancreatic Cancer Treatment.

Increasing evidence has demonstrated that STAT3 phosphorylation at Tyr and Ser is closely associated with the progression and poor prognosis of pancreatic cancer. Herein, we report the function-based screening, SAR studies, and biological activity evaluation of a series of novel STAT3 dual phosphorylation inhibitors with an indole-containing tetra-aromatic heterocycle scaffold. Our efforts led to the discovery of optimal compound among the investigated ones, showing desirable ADME properties and highly potent antitumor activities and . By targeting the STAT3 SH2 domain, significantly blocked p-Tyr and p-Ser and caused the abrogation of the corresponding nuclear transcription and mitochondrial oxidative phosphorylation functions of STAT3 in the low nanomolar range. Except for nanomolar antiproliferation activities , oral treatment of exhibited significant suppressive effects and tolerance in a pancreatic cancer xenograft model, indicating that could be useful for pancreatic cancer treatment as a STAT3 dual phosphorylation inhibitor.