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[Display omitted] In this study, we have designed, synthesized and tested three series of novel dihydropteridone derivatives possessing isoindolin-1-one or isoindoline moieties as potent inhibitors of PLK1/BRD4. Remarkably, most of the compounds showed preferable inhibitory activity against PLK1 and BRD4. Compound SC10 exhibited excellent inhibitory activity with IC 50 values of 0.3 nM and 60.8 nM against PLK1 and BRD4, respectively. Meanwhile, it demonstrated significant anti-proliferative activities against three tumor-derived cell lines (MDA-MB-231 IC 50 = 17.3 nM, MDA-MB-361 IC 50 = 8.4 nM, and MV4-11 IC 50 = 5.4 nM). Moreover, SC10 exhibited moderate rat liver microsomal stability (CLint = 21.3 µL·min−1·mg−1), acceptable pharmacokinetic profile (AUC 0-t = 657 ng·h·mL−1, oral bioavailability of 21.4 %) in Sprague-Dawley rats, reduced hERG toxicity, acceptable PPB and CYP450 inhibition. Further research indicated that SC10 could induce MV4-11 cell arrest at the S phase and apoptosis in a dose-dependent manner. This investigation provided us with an initial point for developing novel anticancer agents as dual inhibitors of PLK1 and BRD4. [ABSTRACT FROM AUTHOR]

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]