Design, synthesis and evaluation of novel cycloalkylthiophene-based aminopyrimidine derivatives as potent PLK1...

PLK1 plays a pivotal role in cell-cycle regulation and has been well-characterized as a promising target for cancer therapy. Here, we synthesized a series of fused-thiophene based aminopyrimidine derivatives, and discovered a novel and potent PLK1 inhibitor compound 7n with an IC₅₀ value of 38.5 nM. Analogue 7n exhibited remarkable antiproliferative efficacy toward HepG2, Huh7, H1299, and A549 cells, and hasn't any noticeable cytotoxic activity on the non-tumoural cell line HEK-293. Further mechanism studies indicated 7n arrested the cell cycle at the G2/M phase and induced apoptosis in HepG2 cells with a concentration-dependent manner. Molecular docking presented that 7n could occupy well the ATP-binding site of PLK1 with a U-shaped conformation. Collectively, these results provide new insights into the further development of fused-thiophene based aminopyrimidines as PLK1 inhibitors.