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

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

机构地区：[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]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

出　　处：《Acta Pharmacologica Sinica》2023年第10期2103-2112,共10页中国药理学报（英文版）

基　　金：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).

摘　　要：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.

关 键 词：cancers PD-1/PD-L1 interaction immune checkpoint inhibitors bis(benzonitrile)dichloroplatinum(II) PD-1 expression alphaLISA assay MC38 colorectal cancer xenografts 

分 类 号：R969.2[医药卫生—药理学]