1 research outputs found
Discovery of the Highly Selective and Potent STAT3 Inhibitor for Pancreatic Cancer Treatment
Signal transducer
and activator of transcription 3 (STAT3) is an
attractive cancer therapeutic target. Unfortunately, targeting STAT3
with small molecules has proven to be very challenging, and for full
activation of STAT3, the cooperative phosphorylation of both tyrosine
705 (Tyr705) and serine 727 (Ser727) is needed. Further, a selective
inhibitor of STAT3 dual phosphorylation has not been developed. Here,
we identified a low nanomolar potency and highly selective small-molecule
STAT3 inhibitor that simultaneously inhibits both STAT3 Tyr705 and
Ser727 phosphorylation. YY002 potently inhibited STAT3-dependent tumor
cell growth in vitro and achieved potent suppression
of tumor growth and metastasis in vivo. More importantly,
YY002 exhibited favorable pharmacokinetics, an acceptable safety profile,
and superior antitumor efficacy compared to BBI608 (STAT3 inhibitor
that has advanced into phase III trials). For the mechanism, YY002
is selectively bound to the STAT3 Src Homology 2 (SH2) domain over
other STAT members, which strongly suppressed STAT3 nuclear and mitochondrial
functions in STAT3-dependent cells. Collectively, this study suggests
the potential of small-molecule STAT3 inhibitors as possible anticancer
therapeutic agents