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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]