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

Area of Science:

• Oncology
• Pharmacology
• Molecular Biology

Background:

• Polo-like kinase 1 (PLK1) is crucial for cell division and implicated in cancer development.
• Targeting PLK1 is a key strategy for anticancer drug development.

Purpose of the Study:

• To develop novel, isoform-specific PLK1 inhibitors using structure-based drug design.
• To evaluate the anticancer efficacy and safety profile of the lead compound B31.

Main Methods:

• Structure-based drug design was employed to synthesize a series of PLK1 inhibitors.
• In vitro assays assessed anticancer potency across various cell lines and kinome selectivity.
• In vivo studies evaluated antileukemic activity in a mouse model.
• Safety and toxicity were assessed using HEK293T cells, hERG channel inhibition assays, and acute toxicity tests.

Main Results:

• Compound B31 emerged as a highly selective, isoform-specific PLK1 inhibitor.
• B31 demonstrated potent in vitro anticancer activity, with an IC50 of 0.08 nM against K562 cells.
• Oral administration of B31 showed significant antileukemic activity in a K562 tumor mouse model.
• B31 exhibited minimal impact on HEK293T cells, weak hERG inhibition, and an excellent safety profile at high doses.

Conclusions:

• Compound B31 is a promising novel antileukemic agent with high potency, selectivity, and an exceptional safety profile.
• The structure-based approach successfully yielded a targeted PLK1 inhibitor with therapeutic potential.