A Novel Allosteric Inhibitor Targets PLK1 in Triple Negative Breast Cancer Cells.

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Polo-like kinase 1 (PLK1) inhibitors show potential for treating triple-negative breast cancer (TNBC).
• Current PLK1 inhibitors have limitations due to non-selective binding to the ATP kinase domain.
• Targeting the PLK1 T-loop offers a novel allosteric inhibition strategy.

Purpose of the Study:

• To develop and evaluate a novel allosteric PLK1 inhibitor targeting the T-loop.
• To assess the efficacy of the inhibitor RK-10 in triple-negative breast cancer cells.
• To investigate RK-10's effects on cell viability, migration, and cell cycle regulation.

Main Methods:

• In silico modeling was used to design the novel compound RK-10.
• Effects of RK-10 were evaluated in MCF-10A and MDA-MB 231 cell lines.
• Assays included assessment of phospho-PLK1 levels, cell viability, wound healing, and cell cycle analysis.

Main Results:

• RK-10 treatment decreased phospho-PLK1 (Thr-210) in both adherent and mammosphere cultures of MDA-MB 231 cells.
• RK-10 significantly inhibited cell viability and attenuated wound healing.
• RK-10 induced S and G2/M cell cycle arrest, correlated with increased p21 expression.

Conclusions:

• A novel allosteric PLK1 inhibitor, RK-10, was successfully developed.
• RK-10 demonstrates anti-proliferative and anti-migratory effects in TNBC models.
• Allosteric PLK1 inhibitors represent a promising therapeutic avenue for TNBC treatment.