Small molecules inhibit STAT3 activation, autophagy, and cancer cell anchorage-independent growth

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Triple-negative breast cancer (TNBC) is an aggressive subtype lacking targeted therapies.
• TNBC is driven by complex signaling pathways and multiple mutations.
• Targeting key kinases involved in TNBC proliferation is a critical unmet need.

Purpose of the Study:

• To discover and characterize a novel small molecule inhibitor for TNBC.
• To investigate the polypharmacology of compound 6, targeting MELK and BMX kinases.
• To evaluate the efficacy of compound 6 in inhibiting TNBC cell growth and related signaling pathways.

Main Methods:

• Synthesis and characterization of compound 6 and its derivatives.
• In vitro kinase inhibition assays (IC50 determination for MELK and BMX).
• Assessment of compound 6's effects on TNBC cell lines (MDA-MB-231, MDA-MB-468) including proliferation, STAT3 phosphorylation, DNA binding, and apoptosis-related protein levels (survivin, Bcl-XL, p21, cyclin A2).
• Autophagy assessment via LC3B-II quantification.

Main Results:

• Compound 6 demonstrated single-digit micromolar IC50 values against MELK and BMX.
• Compound 6 inhibited anchorage-dependent and independent growth of TNBC cells.
• Treatment with compound 6 modulated STAT3 phosphorylation, DNA binding, and levels of apoptosis-related proteins.
• Compound 6 affected autophagy markers (LC3B-II levels).

Conclusions:

• Compound 6 is a potent inhibitor of MELK and BMX kinases.
• The small molecule 6 exhibits anti-proliferative and anti-metastatic potential in TNBC models.
• Compound 6 represents a promising lead for developing novel polypharmacological agents against TNBC.