-driven identification of Pranlukast as a Stabilizer of PD-L1 Homodimers.

INTRODUCTION

Programmed cell death protein 1 (PD-1) and programmed cell death ligand 1 (PD-L1) are critical immune checkpoints in cancer biology. Multiple small-molecule drugs have been developed as inhibitors of the PD-1/PD-L1 axis. Those drugs promote the formation of PD-L1 homodimers, causing their stabilization, internalization, and subsequent degradation. Drug repurposing is a strategy that expedites the clinical translation by identifying new effects of drugs with clinical use. Herein, we aimed to repurpose drugs as inductors of PD-L1 homodimerization and, therefore, as potential inhibitors of PD-L1.

METHODS

We generated a hybrid pharmacophore model by analyzing the structures of reported ligands that induce PD-L1 homodimerization and their target-binding mode. Pharmacophore-matching compounds were selected from a chemical library of Food and Drug Administration (FDA)-approved drugs. Their binding modes to PDL1 homodimers were assessed by molecular docking and the stability of the complexes and the corresponding binding energies were evaluated by molecular dynamics (MD) simulations. Finally, the activity of one drug as promoter of PD-L1 homodimerization was assessed in protein crosslinking assays.

RESULTS

We identified 12 pharmacophore-matching compounds, but only 4 reproduced the binding mode of the reference inhibitors. Further characterization by MD showed that pranlukast, an antagonist of leukotriene receptors that is used to treat asthma, generated stable and energy-favorable interactions with PD-L1 homodimers and induced homodimerization of recombinant PD-L1.

CONCLUSION

Our results suggest that pranlukast inhibits the PD-1/PD-L1 axis, meriting its repurposing as an antitumor drug.