Evaluation Of Biological Activity Of Novel PLK1 Kinase Inhibitors

Polo-like kinase 1(PLK1)belongs to the serine/threonine kinase family,which acts as a regulator of the cell cycle including the mitotic entry and progression.It's crucial for cellular proliferation.PLK1 is expressed primarily during late G2 and M phases in humans and acts as a key regulator of numberous protein substrates in mitosis,in conjuction with CDK1/CyclinB1.Overexpression of PLK1 is tightly assosciated with cancers,which with poor prognosis in a wide range of cancer types.Therefore,PLK1 is a promissing target for the development of anticancer drugs.In this study,we have identified a potent and selective ATP-competitive inhibitor with new structure feature,DZ-06-159-01,which works in an ATP-competivie manner.DZ-06-159-01 exhibited potent antiproliferative activities with IC50s less than 300 nM via inducing G2/M arrest against a panel of human cancer cell lines with overexpression of PLK1.DZ-06-159-01 induced the phenotype of monopolar spindle surrounded by highly condensed chromatin,which is a characteristic phenotype during PLK1 inhibition.In vivo efficacy study revealed that DZ-06-159-01 singinficantly suppressed tumor growth in mouse xenograft model of HepG2..Consisent with in vitro results from cell-based assays,DZ-06-159-01 induced G2/M arrest and apoptosis in vivo.Collectively,we have discovered DZ-06-159-01 as a novel and potent PLK1 inhibitor,which would serve as a promising lead compound for new drug development targeting PLK1.