Structure-Based Discovery of a Highly Selective, Oral Polo-Like Kinase 1 Inhibitor with Potent Antileukemic Activity.

Polo-like kinase 1 (PLK1) plays pivotal roles in cell division and cancer pathogenesis, making it a highly coveted therapeutic target for anticancer strategies. This article reports a series of PLK1 inhibitors developed using a structure-based strategy, culminating in the discovery of compound B31, a novel isoform-specific PLK1 inhibitor with excellent kinome selectivity. In vitro, this compound exhibited superior anticancer potency across a broad spectrum of cell lines, particularly against K562, achieving a remarkable IC₅₀ value of 0.08 nM. In a mouse model harboring subcutaneous K562 tumors, oral administration of B31 at dosages of 10 or 20 mg/kg twice weekly exhibited remarkable antileukemic activity. B31 had minimal impact on HEK293T cells and very weak inhibitory activity against the hERG channel. Furthermore, in the acute toxicity test, this compound demonstrated an extraordinary safety profile even at a dosage of 500 mg/kg, highlighting its potential as a novel antileukemic agent.