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  3. Design, synthesis, and biological evaluation of novel molecules as potent inhibitors of PLK1

Design, synthesis, and biological evaluation of novel molecules as potent inhibitors of PLK1

  • Bioorg Chem. 2023 Oct:139:106711. doi: 10.1016/j.bioorg.2023.106711.
Jing Lu 1,  Hui Lei 2,  Xinfa Bai 2,  Wenyan Wang 1,  Chunjiao Liu 2,  Yifei Yang 1,  Fangxia Zou 1,  Lin Wang 1,  Yunjie Wang 1,  Guangying Du 1,  Xin Wang 1,  Cuicui Sun 2,  Lisha Yu 2,  Mingxu Ma 1,  Liang Ye 3,  Hongbo Wang 1,  Jingwei Tian 4,  Jianzhao Zhang 5
Affiliations

Affiliations

  • 1 School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai 264005, PR China.
  • 2 R & D Center, Luye Pharma Group Ltd., Yantai 264003, PR China.
  • 3 School of Public Health and Management, Binzhou Medical University, Yantai, PR China. Electronic address: yeliang@luye.com.
  • 4 School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai 264005, PR China. Electronic address: tianjingwei@luye.com.
  • 5 School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai 264005, PR China. Electronic address: zhangjianzhao@163.com.
PMID: 37473479 DOI: 10.1016/j.bioorg.2023.106711
Abstract

Polo-like kinase 1 (PLK1) is an attractive therapeutic target for the treatment of tumors, as it is an essential cell-cycle regulator frequently overexpressed in tumor tissues. PLK1 can promote tumor invasion and metastasis, and is often associated with poor prognosis in Cancer patients. However, no PLK1 Inhibitor has been granted marketing approval until now. Therefore, more potentially promising PLK1 inhibitors need to be investigated. In this study, a series of novel inhibitors targeting PLK1 was designed and optimized derived from a new scaffold. After synthesis and characterization, we obtained the structure-activity relationship and led to the discovery of the most promising compound 30e for PLK1. The antiproliferative activity against HCT116 cells (IC50 = 5 nM versus 45 nM for onvansertib) and the cellular permeability and efflux ratio were significantly improved (PappA→B = 2.03 versus 0.345 and efflux ratio = 1.65 versus 94.7 for 30e and onvansertib, respectively). Further in vivo studies indicated that 30e had favorable antitumor activity with 116.2% tumor growth inhibition (TGI) in comparison with TGI of 43.0% for onvansertib. Furthermore, 30e improved volume of tumor tissue distribution in mice as compared to onvansertib. This initial study on 30e holds promise for further development of an antitumor agent.

Keywords

Anti-tumor; Core scaffold hopping; PLK1 inhibitor; Structure-activity relationship.

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