Abstract
PLK1 is essential for cell cycle regulation and proliferation, and its elevated expression in prostate cancer is associated with high tumour grade. Therefore, PLK1 inhibition is considered a promising strategy for the treatment of prostate cancer. Here, we identified five compounds (Hits 1-5) targeting the kinase domain (KD) of PLK1 using a combined virtual screening approach. Hits 1-5 all had picomolar (pM) inhibitory potency against PLK1. Notably, Hit-4 showed the strongest inhibitory activity against PLK1 (IC(50) = 22.61 ± 1.12 pM) and displayed high selectivity for PLK1. Meanwhile, molecular dynamics (MD) simulations revealed that the complex formed by Hit-4 and PLK1 remained stable. Importantly, Hit-4 exhibited potent inhibitory effects on the proliferation of DU-145 prostate cancer cells (IC(50) = 0.09 ± 0.01 nM). In conclusion, Hit-4 is a potent and highly selective antitumor candidate with therapeutic potential for prostate cancer.