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

Abstract

Increasing evidence has demonstrated that STAT3 phosphorylation at Tyr⁷⁰⁵ and Ser⁷²⁷ 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 <b>4c</b> among the investigated ones, showing desirable ADME properties and highly potent antitumor activities <i>in vitro</i> and <i>in vivo</i>. By targeting the STAT3 SH2 domain, <b>4c</b> significantly blocked p-Tyr⁷⁰⁵ and p-Ser⁷²⁷ 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 <i>in vitro</i>, oral treatment of <b>4c</b> exhibited significant suppressive effects and tolerance in a pancreatic cancer xenograft model, indicating that <b>4c</b> could be useful for pancreatic cancer treatment as a STAT3 dual phosphorylation inhibitor.