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

作者全名："Wang, Rui-na; Yu, Qian; Wang, Xiao-bo; Zhu, Di; Li, Guo-long; Li, Zeng-xia; Jiang, Wei; Li, Wei; Dang, Yong-jun"

作者地址："[Wang, Rui-na; Yu, Qian; Wang, Xiao-bo; Zhu, Di; Li, Zeng-xia; Jiang, Wei; Dang, Yong-jun] Fudan Univ, Shanghai Med Coll, Sch Basic Med Sci, Dept Biochem & Mol Biol,Key Lab Metab & Mol Med,Mi, Shanghai 200032, Peoples R China; [Li, Guo-long; Li, Wei] China Pharmaceut Univ, Dept Med Chem, Nanjing 211198, Peoples R China; [Dang, Yong-jun] Chongqing Med Univ, Affiliated Hosp 2, Inst Life Sci, Ctr Novel Target & Therapeut Intervent, Chongqing 400016, Peoples R China"

通信作者："Jiang, W; Dang, YJ (通讯作者)，Fudan Univ, Shanghai Med Coll, Sch Basic Med Sci, Dept Biochem & Mol Biol,Key Lab Metab & Mol Med,Mi, Shanghai 200032, Peoples R China.; Li, W (通讯作者)，China Pharmaceut Univ, Dept Med Chem, Nanjing 211198, Peoples R China.; Dang, YJ (通讯作者)，Chongqing Med Univ, Affiliated Hosp 2, Inst Life Sci, Ctr Novel Target & Therapeut Intervent, Chongqing 400016, Peoples R China."

来源：ACTA PHARMACOLOGICA SINICA

ESI学科分类：PHARMACOLOGY & TOXICOLOGY

WOS号：WOS:000988722200002

JCR分区：Q1

影响因子：8.2

年份：2023

卷号：　

期号：　

开始页：　

结束页：　

文献类型：Article; Early Access

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

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 mu M. 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 mu M). 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 mu M) 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."

基金机构："National Key Research and Development Program of China [2022YFC2804800]; National Natural Science Foundation of China [22137002, 21877016, 82273021, 81972621, 21977115]; Science and Technolog Commission of Shanghai Municipality [20JC1410900]; University Innovation Research Group in Chongqing [CXQT21016]; Chongqing Talent Program Project [CQYC20200302119]; High-Level Innovation Platform Cultivation Plan of Chongqing; Joint Fund of the Natural Science Innovation and Development Foundation of Chongqing"

基金资助正文："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)."