High-throughput virtual screening, identification and in vitro biological evaluation of novel inhibitors of PLK1 and NRP1.

Abstract

Overexpression of PLK1 and NRP1 correlate with enhanced proliferative activity in lung cancer cells, thus the development of dual-target PLK1/NRP1 inhibitors holds great therapeutic promise. In this study, five compounds (PLN 1-5) targeting both PLK1 and NRP1 were identified using a multi-step virtual screening approach. PLN-5 showed nanomolar inhibitory potency against PLK1 (IC₅₀ = 2.07 ± 0.13 nM) and NRP1 (IC₅₀ = 5.15 ± 0.24 nM), exceeding the positive controls onvansertib and EG00229 by approximately 9-fold and 124-fold, respectively. Molecular dynamics (MD) simulations revealed that PLN-5 maintained a stable binding to the active sites of PLK1 and NRP1. Importantly, MTT assays showed that PLN-5 had significant antiproliferative activity (IC₅₀ = 0.27 ± 0.02 μM) against human lung cancer cells, with no significant inhibitory effect on normal lung cells. In conclusion, these results demonstrate the therapeutic potential of PLN-5 as a dual-targeting antitumor agent that warrants further development.