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A Novel Allosteric Inhibitor Targets PLK1 in Triple Negative Breast Cancer Cells
Jankiben R Patel1, Prasad Thangavelu2, Renee M Terrell1
1Division of Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Institutes of Public Health, Florida A&M University, 1415 S. Martin L. King Jr. Blvd, Tallahassee, FL 32307, USA.
Abstract:
While Polo-like kinase 1 (PLK1) inhibitors have shown promise in clinical settings for treating triple-negative breast cancer tumors and other solid tumors, they are limited by their ability to bind non-selectively to the ATP kinase domain. Therefore, we sought to develop a PLK1 allosteric inhibitor targeting the PLK1 T-loop (a switch responsible for activation) and evaluate its effects in triple-negative breast cancer cells. A novel compound, RK-10, was developed based on an in silico model, and its effects on specificity, viability, migration, and cell cycle regulation in MCF-10A and MDA-MB 231 cells were evaluated. When MDA-MB 231 cells were treated with 0−50 µg/mL RK-10, phospho-PLK1 (Thr-210) was decreased in cells cultured adherently and cells cultured as mammospheres. RK-10 significantly inhibited viability after 24 h; however, by 48 h, 25−50 µM RK-10 caused >50% reduction. RK-10 attenuated wound healing by up to 99.7% and caused S and G2/M cell cycle arrest, which was associated with increased p21 expression. We developed a novel allosteric inhibitor which mediates anti-proliferative and anti-migratory properties through targeting phospho-PLK1 (Thr-210) in mammospheres and causing S phase and G2/M cell cycle arrest. Further development of PLK1 allosteric inhibitors may be a promising approach for TNBC treatment.
Insights
A new Polo-like kinase 1 (PLK1) allosteric inhibitor, RK-10, effectively targets triple-negative breast cancer (TNBC) cells. RK-10 reduces cell viability and migration while inducing cell cycle arrest, offering a promising new therapeutic strategy for TNBC.
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.
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