2. Academic Validation
  3. Bis(benzonitrile) dichloroplatinum (II) interrupts PD-1/PD-L1 interaction by binding to PD-1

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

  • Acta Pharmacol Sin. 2023 May 16. doi: 10.1038/s41401-023-01092-9.
Rui-Na Wang # 1,  Qian Yu # 1,  Xiao-Bo Wang 1,  Di Zhu 1,  Guo-Long Li 2,  Zeng-Xia Li 1,  Wei Jiang 3,  Wei Li 4,  Yong-Jun Dang 5 6
Affiliations

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.
  • 2 Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, 211198, China.
  • 3 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. jiangw@fudan.edu.cn.
  • 4 Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, 211198, China. wli@cpu.edu.cn.
  • 5 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. yjdang@cqmu.edu.cn.
  • 6 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. yjdang@cqmu.edu.cn.
  • # Contributed equally.
PMID: 37193754 DOI: 10.1038/s41401-023-01092-9
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.

Keywords

MC38 colorectal cancer xenografts; PD-1 expression; PD-1/PD-L1 interaction; alphaLISA assay; bis(benzonitrile) dichloroplatinum (II); cancers; immune checkpoint inhibitors.

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