Affiliation:
1. School of Pharmacy, Hebei University of Chinese Medicine, Shijiazhuang 050200, China
2. Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
3. School of Chemical and Pharmaceutical Engineering, Hebei University of Science and Technology, Shijiazhuang 050018, China
4. School of Pharmacy, Guilin Medical University, Guilin 541199, China
Abstract
Background:
Polo-like kinase 1 (PLK1), a validated target for tumor therapy, plays a key role in mitosis and is over-expressed in many tumors. In addition to its N-terminal kinase domain, PLk1 also harbors a C-terminal polo-box domain (PBD).
Objective:
A candidate based on PLK1-PBD was developed as a promising compound for future development.
Method:
Seventeen small molecule PLK1-PBD inhibitors were designed, synthesized and evaluated for PLK1-PBD inhibitory activities by fluorescence polarization (FP) assay. The compounds with better inhibitory activities were further assessed for their anti-proliferative activities using a CCK-8 method.
Results:
The inhibitory rates of compounds 7a, 7d, 14a, 14d, 14e and 14f exceeded 98%. The IC50 values of compounds 7d, 14d, 14e, and 14f were 0.73 μM, 0.67 μM, 0.89 μM and 0.26 μM, proving better than MCC1019. Compound 14f showed the best inhibitory activity (IC50: 0.26 μM) and antiproliferative activities against three cancer cell lines (HeLa, HepG2 and MG63). Especially, compound 14f also exhibited acceptable safety profiles in the human ether-a-go-go related gene (hERG) and normal cell tests. The results of docking and prediction studies indicated that compound 14f had a high binding affinity to the target, with good drug-like absorption, distribution, metabolism, elimination, and toxicity (ADMET) properties.
Conclusion:
Compound 14f can be a promising compound for future development.
Publisher
Bentham Science Publishers Ltd.
Subject
Drug Discovery,Pharmaceutical Science,Molecular Medicine