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

Acta Pharmacologica Sinica volume 44, pages 2103–2112 (2023)Cite this article

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.

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Fig. 1: Establishment and optimization of AlphaLISA PD-1/PD-L1 interaction assay.
Fig. 2: Cisplatin in DMSO solvent is a potential PD-1/PD-L1 inhibitor.
Fig. 3: Bis(benzonitrile) dichloroplatinum (II) and dichloro(1,5-cyclooctadiene) platinum (II) block the PD-1/PD-L1 interaction.
Fig. 4: Bis(benzonitrile) dichloroplatinum (II) binds to PD-1 and blocks PD-1/PD-L1 signaling pathway.
Fig. 5: Bis(benzonitrile) dichloroplatinum (II) inhibits tumor growth and increases tumor-infiltrating T cells numbers and activity.

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Acknowledgements

This work was financially supported by the National Key Research and Development Program of China (No. 2022YFC2804800 to WJ), the National Natural Science Foundation of China (22137002, 21877016 to YJD; 82273021, 81972621 to WJ; 21977115 to WL), Science and TechnologCommission of Shanghai Municipality (Grant 20JC1410900 to YJD), University Innovation Research Group in Chongqing (No. CXQT21016 to YJD), Chongqing Talent Program Project (No. CQYC20200302119 to YJD), High-Level Innovation Platform Cultivation Plan of Chongqing (to YJD), Joint Fund of the Natural Science Innovation and Development Foundation of Chongqing (to YJD).

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  1. These authors contributed equally: Rui-na Wang, Qian Yu

Authors and Affiliations

  1. Key Laboratory of Metabolism and Molecular Medicine, The Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, 200032, China

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

  2. Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, 211198, China

    Guo-long Li & Wei Li

  3. Center for Novel Target and Therapeutic Intervention, Institute of Life Sciences, The Second Affiliated Hospital of Chongqing Medical University, Chongqing Medical University, Chongqing, 400016, China

    Yong-jun Dang

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Contributions

YJD initiates the project, YJD, WJ, and WL designed and supervised the project; RNW, XBW, QY, DZ, and GLL did experiments and analyzed data; RNW, XBW, and QY contributed to molecular biological and animal experiments; GLL contributed to chemical synthesis of derivatives of bis(benzonitrile) dichloroplatinum (II); the paper was written by RNW and reviewed by WJ, ZXL, WL, and YJD.

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Correspondence to Wei Jiang, Wei Li or Yong-jun Dang.

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Wang, Rn., Yu, Q., Wang, Xb. et al. Bis(benzonitrile) dichloroplatinum (II) interrupts PD-1/PD-L1 interaction by binding to PD-1. Acta Pharmacol Sin 44, 2103–2112 (2023). https://doi.org/10.1038/s41401-023-01092-9

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