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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 IC 50 value of 0.45 nM and significant anti-proliferative activities against four tumor-derived cell lines (MCF-7 IC 50 = 8.64 nM, HCT-116 IC 50 = 26.0 nM, MDA-MB-231 IC 50 = 14.8 nM and MV4-11 IC 50 = 47.4 nM) with better pharmacokinetic characteristics than BI2536 in mice (AUC 0-t = 11 227 ng h mL−1 vs 556 ng h mL−1). Moreover, 21g exhibited moderate liver microsomal stability and excellent pharmacokinetic profile (AUC 0-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. [Display omitted] • Novel dihydropteridone derivatives were designed and synthesized for PLK1 inhibitors. • 21 g exhibited an IC 50 value of 0.45 nM against PLK1, notably antiproliferative activity. • 21 g exhibited excellent PK profile, acceptable PPB, and improved PLK1 selectivity. • 21 g was well tolerated at a dose of 20 mg/kg with no acute toxicity. [ABSTRACT FROM AUTHOR]