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Bis(benzonitrile) dichloroplatinum (II) interrupts PD-1/PD-L1 interaction by binding to PD-1

   
@article{APS10910,
	author = {Rui-na Wang and Qian Yu and Xiao-bo Wang and Di Zhu and Guo-long Li and Zeng-xia Li and Wei Jiang and Wei Li and Yong-jun Dang},
	title = {Bis(benzonitrile) dichloroplatinum (II) interrupts PD-1/PD-L1 interaction by binding to PD-1},
	journal = {Acta Pharmacologica Sinica},
	volume = {44},
	number = {10},
	year = {2023},
	keywords = {},
	abstract = {Checkpoint inhibitors such as PD-1/PD-L1 antibody therapeutics are a promising option for the treatment of multiple cancers. Due to the inherent limitations of antibodies, great efforts have been devoted to developing small-molecule PD-1/PD-L1 signaling pathway inhibitors. In this study we established a high-throughput AlphaLISA assay to discover small molecules with new skeletons that could block PD-1/PD-L1 interaction. We screened a small-molecule library of 4169 compounds including natural products, FDA approved drugs and other synthetic compounds. Among the 8 potential hits, we found that cisplatin, a first-line chemotherapeutic drug, reduced AlphaLISA signal with an EC50 of 8.3 ± 2.2 μM. Furthermore, we showed that cisplatin-DMSO adduct, but not semplice cisplatin, inhibited PD-1/PD-L1 interaction. Thus, we assessed several commercial platinum (II) compounds, and found that bis(benzonitrile) dichloroplatinum (II) disturbed PD-1/PD-L1 interaction (EC50 = 13.2 ± 3.5 μM). Its inhibitory activity on PD-1/PD-L1 interaction was confirmed in co-immunoprecipitation and PD-1/PD-L1 signaling pathway blockade bioassays. Surface plasmon resonance assay revealed that bis(benzonitrile) dichloroplatinum (II) bound to PD-1 (KD = 2.08 μM) but not PD-L1. In immune-competent wild-type mice but not in immunodeficient nude mice, bis(benzonitrile) dichloroplatinum (II) (7.5 mg/kg, i.p., every 3 days) significantly suppressed the growth of MC38 colorectal cancer xenografts with increasing tumor-infiltrating T cells. These data highlight that platinum compounds are potential immune checkpoint inhibitors for the treatment of cancers.},
	issn = {1745-7254},	url = {http://www.chinaphar.com/article/view/10910}
}