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 <b>B31</b>, a novel isoform-specific PLK1 inhibitor with excellent kinome selectivity. <i>In vitro</i>, 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 <b>B31</b> at dosages of 10 or 20 mg/kg twice weekly exhibited remarkable antileukemic activity. <b>B31</b> 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.