Journal Article

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

Li, Guo-long, Yu, Qian, Li, Zeng-xia, Wang, Rui-na, Jiang, Wei, Dang, Yong-jun, Wang, Xiao-bo, Li, Wei, Zhu, Di

2023

Overview

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 EC 50 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 (EC 50  = 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 ( K D  = 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.

• Publisher: Springer Nature Singapore,Nature Publishing Group
• Subject: Animals / Antibodies / B7-H1 Antigen - metabolism / Benzonitrile / Biomedical and Life Sciences / Biomedicine / Chemotherapy / Cisplatin / Cisplatin - pharmacology / Cisplatin - therapeutic use / Colorectal cancer / FDA approval / Humans / Immune checkpoint inhibitors / Immune Checkpoint Inhibitors - pharmacology / Immunodeficiency / Immunology / Immunoprecipitation / Immunosuppressive agents / Internal Medicine / Laboratory animals / Lung cancer / Lymphocytes T / Medical Microbiology / Mice / Mice, Nude / Natural products / Neoplasms - drug therapy / Nitriles - pharmacology / Organoplatinum Compounds - pharmacology / PD-1 protein / PD-L1 protein / Peptides / Permeability / Pharmacology/Toxicology / Plasmids / Platinum compounds / Programmed Cell Death 1 Receptor / Signal transduction / Surface plasmon resonance / Vaccine