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

Yang Xia ¹, Yuting Chang ¹, Lixia Guan ²

⁰Department of Oncology, The Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou, China.

Journal of Enzyme Inhibition and Medicinal Chemistry +

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August 18, 2025

View abstract on PubMed

Summary

A novel dual-targeting inhibitor, PLN-5, effectively reduces lung cancer cell proliferation by inhibiting PLK1 and NRP1. This compound shows significant therapeutic potential for lung cancer treatment with minimal impact on normal cells.

Area Of Science

Oncology
Pharmacology
Computational Chemistry

Background

Overexpression of Polo-like kinase 1 (PLK1) and Neuropilin-1 (NRP1) is linked to increased proliferation in lung cancer.
Targeting both PLK1 and NRP1 simultaneously presents a promising therapeutic strategy for lung cancer.

Purpose Of The Study

To identify and characterize novel dual-targeting inhibitors of PLK1 and NRP1.
To evaluate the preclinical efficacy of identified compounds against human lung cancer cells.

Main Methods

A multi-step virtual screening approach was employed to identify potential dual inhibitors.
In vitro assays, including IC50 determinations for PLK1 and NRP1 inhibition, were performed.
Molecular dynamics (MD) simulations assessed binding stability.
MTT assays evaluated antiproliferative activity against lung cancer and normal lung cells.

Main Results

Five compounds (PLN 1-5) targeting both PLK1 and NRP1 were identified.
PLN-5 demonstrated potent inhibition of PLK1 (IC50 = 2.07 nM) and NRP1 (IC50 = 5.15 nM), outperforming positive controls.
MD simulations confirmed stable binding of PLN-5 to the active sites of PLK1 and NRP1.
PLN-5 exhibited significant antiproliferative effects on human lung cancer cells (IC50 = 0.27 μM) without affecting normal lung cells.

Conclusions

PLN-5 is a potent dual-targeting inhibitor of PLK1 and NRP1.
PLN-5 demonstrates significant antiproliferative activity against lung cancer cells in vitro.
PLN-5 warrants further investigation as a potential therapeutic agent for lung cancer.

Keywords:

Polo-like kinase-1 dual-targeting inhibitors lung cancer neuropilin-1 virtual screening