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

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 4c among
the investigated ones, showing desirable ADME properties and highly
potent antitumor activities in vitro and in vivo. By targeting the STAT3 SH2 domain, 4c 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 in vitro, oral treatment of 4c exhibited significant
suppressive effects and tolerance in a pancreatic cancer xenograft
model, indicating that 4c could be useful for pancreatic
cancer treatment as a STAT3 dual phosphorylation inhibitor.