Discovery of novel dihydropteridone derivatives as orally bioavailable PLK1 inhibitors with reduced hERG inhibitory activity for acute myeloid leukemia treatment.

Polo like kinase 1 (PLK1) is a serine/threonine kinase that plays an important role in multiple phases of the cell cycle, inhibiting its activity has been considered an effective treatment for acute myeloid leukemia (AML). Here, we reported a series of highly potent PLK1 inhibitors. Among them, compound WD6 was identified as the most promising PLK1 inhibitor, with an IC value of 0.27 nM and greatly reduced hERG affinity, with 12.78 % inhibition at 10 μM. Compound WD6 displayed significant anti-proliferative activities against MV4-11 (IC = 23.3 nM), excellent pharmacokinetic properties (t = 7.59 h, AUC = 29300 ng h mL and F = 35.1 %), good PPB and low risk of drug-drug interactions. In vivo, oral administration of compound WD6 at a dose of 20 mg/kg effectively suppressed the tumor growth in the MV4-11 xenograft mouse model. Further research indicated that WD6 exhibited excellent kinase selectivity, arresting MV4-11 cells at G2 phase, inducing apoptosis in a dose-dependent manner and down-regulating the transcription of the proliferation-related oncogene c-MYC. These results showed that compound WD6 has the potential to be a promising drug candidate for treating AML.