Design, synthesis and biological activity evaluation of a novel selective inhibitor in PLK1 with acyl or sulfonyl substituted dihydroindole structure

Polo-like kinase 1 (PLK1), the most well-studied kinase in the Polo like kinase (PLK) family, is a class of serine/threonine protein kinases that play a crucial role in cell cycle regulation, and is widely present in eukaryotes. PLK1 is considered a potential target for oncology drug development. We have synthesized and tested a novel acyl or sulfonyl groups-based derivative with dihydroindole as a potent inhibitor of PLK1. Among them, compound B7 exhibits good inhibitory activity against PLK1 with an IC₅₀ value of 0.25 nM. At the same time, it showed significant antiproliferative activity against three tumor-derived cell lines (MDA-MB-231 IC₅₀ = 72.5 nM, MDA-MB-361 IC₅₀ = 316 nM, MV-411 IC₅₀ = 32.1 nM). Further investigation showed that B7 could arrest MV4-11 cells in G2 phase and induce Apoptosis in a dose-dependent manner. And B7 can be stable under simulated gastric acid environmental conditions, and acceptable CYP 450 inhibition. Moreover, B7 has excellent plasma protein binding rates in human, rat, and mouse. The pharmacokinetic profile of B7 in rats is also superior to that of BI 2536 (AUC_0-t = 578 ng·h·mL^-1 vs 283 ng·h·mL^-1), and the bioavailability of B7 is 20.1 %, and no apparent toxicity was observed in the acute toxicity assay (20 mg/kg). These results suggest that B7 is a promising PLK1 Inhibitor.

Anticancer activity; Dihydrobiopterin; PLK1 inhibitors; Structure activity relationship.