Design, synthesis, and biological evaluation of novel dihydropteridone derivatives possessing oxadiazoles moiety as potent inhibitors of PLK1.

Abstract

Polo like kinase 1 (PLK1) is a serine/threonine kinase that is widely distributed in eukaryotic cells and plays an important role in multiple phases of the cell cycle. Its importance in tumorigenesis has been increasingly recognized in recent years. Herein, we describe the optimization of a series of novel dihydropteridone derivatives (13a-13v and 21g-21l) possessing oxadiazoles moiety as potent inhibitors of PLK1. Compound 21g exhibited improved PLK1 inhibitory capability with an IC50 value of 0.45 nM and significant anti-proliferative activities against four tumor-derived cell lines (MCF-7 IC50 = 8.64 nM, HCT-116 IC50 = 26.0 nM, MDA-MB-231 IC50 = 14.8 nM and MV4-11 IC50 = 47.4 nM) with better pharmacokinetic characteristics than BI2536 in mice (AUC0-t = 11 227 ng h mL-1vs 556 ng h mL-1). Moreover, 21g exhibited moderate liver microsomal stability and excellent pharmacokinetic profile (AUC0-t = 11227 ng h mL-1, oral bioavailability of 77.4%) in Balb/c mice, acceptable PPB, improved PLK1 inhibitory selectivity, and no apparent toxicity was observed in the acute toxicity assay (20 mg/kg). Further investigation showed that 21 g could arrest HCT-116 cells in G2 phase and induce apoptosis in a dose-dependent manner. These results indicate that 21g is a promising PLK1 inhibitor.

• Authors: Zhiwei Li, Sheng Mei, Jiuyu Liu, Jingxuan Huang, Hao Yue, Tingjie Ge, Kang Wang, Xinzi He, Yu-Cheng Gu, Changliang Hu, Minghui Tong, Xuan Shi, Yanfang Zhao, Yajing Liu, Mingze Qin, Ping Gong, Yunlei Hou
• Journal: European journal of medicinal chemistry (Eur J Med Chem) Vol. 251 Pg. 115242 (May 05 2023) ISSN: 1768-3254 [Electronic] France
• PMID: 36889251 (Publication Type: Journal Article)
• Copyright: Copyright © 2023. Published by Elsevier Masson SAS.

Chemical References

• Antineoplastic Agents
• Protein Kinase Inhibitors
• Cell Cycle Proteins
• Protein Serine-Threonine Kinases

Topics

• Mice
• Animals
• Cell Proliferation
• Antineoplastic Agents (pharmacology)
• Protein Kinase Inhibitors
• Cell Cycle Proteins
• Protein Serine-Threonine Kinases
• Cell Line, Tumor
• Apoptosis