| Autor: |
Patel JR; Division 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., Thangavelu P; College of Pharmacy, University of Findlay, 1000 N Main St., Findlay, OH 45840, USA., Terrell RM; Division 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., Israel B; Division 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., Sarkar AB; College of Pharmacy, University of Findlay, 1000 N Main St., Findlay, OH 45840, USA., Davidson AM; Division 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., Zhang K; Department of Computer Science, Division of Mathematical and Physical Sciences, College of Arts and Sciences, Xavier University of Louisiana, New Orleans, LA 70125, USA., Khupse R; College of Pharmacy, University of Findlay, 1000 N Main St., Findlay, OH 45840, USA., Tilghman SL; Division 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. |
| Abstrakt: |
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. |
