Bt354 as a new STAT3 signaling pathway inhibitor against triple negative breast cancer

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• Constitutive activation of the signal transducer and activator of transcription 3 (STAT3) signaling pathway is implicated in human cancer development.
• Targeting the STAT3 pathway presents a promising therapeutic strategy for STAT3-dependent cancers.

Purpose of the Study:

• To identify novel small-molecule inhibitors of the STAT3 signaling pathway.
• To evaluate the anticancer potential of a newly identified compound, Bt354, in preclinical models.

Main Methods:

• Screening of 1563 compounds to identify STAT3 inhibitors.
• In vitro assays including dual luciferase assay to assess STAT3 activity and cell proliferation assays.
• In vivo studies using xenograft mouse models to evaluate tumor growth inhibition.
• Computational modeling to predict the binding interaction of Bt354 with STAT3.

Main Results:

• Bt354 was identified as a potent inhibitor of STAT3 activity, significantly suppressing STAT3 phosphorylation at Y705.
• Bt354 demonstrated dose- and time-dependent inhibition of cancer cell proliferation and induced apoptosis and G2/M cell cycle arrest.
• In vivo studies showed that Bt354 inhibited tumor growth in xenograft models without adverse effects on body weight.
• Computational modeling indicated that Bt354 binds to the SH2 domain of STAT3.

Conclusions:

• Bt354 is a novel small-molecule inhibitor of the STAT3 signaling pathway.
• Bt354 exhibits significant anticancer activity in vitro and in vivo, particularly in triple-negative breast cancer models.
• Bt354 represents a potential therapeutic agent for STAT3-activated cancers.