Purpose: Pancreatic cancer is the worst prognoses among all human cancers, and novel effective treatments are urgent needed. Signal transducer and activator of transcription 3 (STAT3) has been demonstrated a promising target for pancreatic cancer. While, selectively targeted STAT3 with small molecule remains been challenging. Experimental Design: To specifically identify STAT3 inhibitors, more than 1.3 million compounds were screened by structure-based virtual screening and confirmed with the direct binding assay. The amino acid residues that WB436B bound to were verified by induced-fit molecular docking simulation, rosetta ligand computations and site-directed mutagenesis. On target effects of WB436B were examined by microscale thermophoresis, surface plasmon resonance, in vitro kinase assay, RNA sequencing and selective cell growth inhibition assessment. In vivo studies performed in four animal models to evaluate effects of WB436B on tumor growth and metastasis. Kaplan–Meier analyses were used to assess survival. Results: WB436B selectively bound to STAT3 over other STAT families protein, and in vitro anti-tumor activities were improved by 10-1000 fold than the representative STAT3 inhibitors. WB436B selectively inhibits STAT3-Tyr705 phosphorylation, STAT3 target gene expression, and the viability of STAT3-dependent pancreatic cancer cells. WB436B significantly suppresses tumor growth and metastasis in vivo and prolongs survival of tumor-bearing mice. Mechanistic studies showed that WB436B have unique binding sites located in STAT3 Src Homology 2 (SH2) domain. Conclusions: Our work presents the First-in-class selective STAT3 inhibitor WB436B as a potential therapeutic candidate for the treatment of pancreatic cancer.
Accumulating evidence has documented that STAT3 phosphorylation
at Tyr705 and Ser727 jointly promotes the initiation
and progression of gastric cancer. However, most reported STAT3 inhibitors
have mainly focused on suppressing STAT3 phosphorylation at Tyr705 while ignoring the tumorigenic effects of phosphorylation
at Ser727. Herein, we described the design, synthesis,
and structure–activity relationship studies on a series of
triaromatic heterocyclic derivatives as potent dual phosphorylation
STAT3 inhibitors. These efforts led to the discovery of the best compound 3h (HP590) among the investigated ones, a novel,
highly potent, and orally bioavailable STAT3 inhibitor possessing
lower nanomolar inhibitory activity toward p-Tyr705 and
p-Ser727. Target validation revealed that HP590 selectively targets STAT3 to remarkably inhibit its canonical and
noncanonical activation and corresponding biological functions, thereby
resulting in the growth inhibition of gastric cancer in vitro and
in vivo, highlighting the therapeutic potential of dual phosphorylation
STAT3 inhibitors for gastric cancer.
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.
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