Disabling the Nuclear Translocalization of RelA/NF-κB by a Small Molecule Inhibits Triple-Negative Breast Cancer...

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Constitutive activation of Nuclear Factor-kappa B (NF-κB) drives cancer progression, drug resistance, and recurrence in various cancers, including breast cancer.
• NF-κB activation involves the nuclear translocation of RelA, a key transcription factor that regulates genes critical for cell function.
• Triple-negative breast cancer (TNBC) exhibits constitutively active NF-κB with elevated nuclear RelA, correlating with chemotherapy response, yet lacks specific inhibitors for RelA nuclear translocation.

Purpose of the Study:

• To develop a novel small-molecule inhibitor targeting RelA nuclear translocation.
• To evaluate the efficacy of the developed inhibitor in preclinical models of triple-negative breast cancer.

Main Methods:

• A structure-based drug design approach was employed to create a small molecule inhibitor.
• Biophysical techniques, including isothermal titration calorimetry and microscale thermophoresis, confirmed the molecule's specific binding to RelA.
• In vitro efficacy was assessed using TNBC cell lines (MDA-MB-231, MDA-MB-468), and in vivo efficacy was evaluated in a human TNBC xenograft model.

Main Results:

• The small molecule, designated CRL1101, demonstrated specific binding to RelA, as confirmed by biophysical assays.
• CRL1101 effectively inhibited RelA nuclear translocation in breast cancer cells in vitro.
• Significant reduction in breast tumor growth was observed in the TNBC xenograft model treated with CRL1101.

Conclusions:

• CRL1101 represents a potential new therapeutic agent for NF-κB-targeted treatment of TNBC.
• Inhibiting the nuclear translocation of shuttling transcription factors may serve as a broadly applicable strategy in cancer drug development.