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Novel Small-MoleculenPD-L1 Inhibitor Induces PD-L1nInternalization and Optimizes the Immune Microenvironment 新型小分子nPD-L1抑制剂诱导PD-L1内化并优化免疫微环境

Figshare Pub Date : 2022-12-29 DOI: 10.1021/acs.jmedchem.2c01801.s006

Chengliang Sun (715954), Mingxiao Yin (14308646), Yao Cheng (447917), Zean Kuang (14308649), Xiaojia Liu (547710), Gefei Wang (498248), Xiao Wang (19312), Kai Yuan (289810), Wenjian Min (11560191), Jingwen Dong (7464395), Yi Hou (148620), Lingrong Hu (14308652), Guoyu Zhang (3423560), Wenli Pei (2304454), Liping Wang (33601), Yanze Sun (14308655), Xinmiao Yu (568132), Yibei Xiao (11560194), Hongbin Deng (3621134), Peng Yang (296696)

{"title":"Novel Small-MoleculenPD-L1 Inhibitor Induces PD-L1nInternalization and Optimizes the Immune Microenvironment","authors":"Chengliang Sun (715954), Mingxiao Yin (14308646), Yao Cheng (447917), Zean Kuang (14308649), Xiaojia Liu (547710), Gefei Wang (498248), Xiao Wang (19312), Kai Yuan (289810), Wenjian Min (11560191), Jingwen Dong (7464395), Yi Hou (148620), Lingrong Hu (14308652), Guoyu Zhang (3423560), Wenli Pei (2304454), Liping Wang (33601), Yanze Sun (14308655), Xinmiao Yu (568132), Yibei Xiao (11560194), Hongbin Deng (3621134), Peng Yang (296696)","doi":"10.1021/acs.jmedchem.2c01801.s006","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.2c01801.s006","url":null,"abstract":"Blocking the PD-1/PD-L1 interaction has become an importantnstrategynfor tumor therapy, which has shown outstanding therapeutic effectsnin clinical settings. However, unsatisfactory response rates and immune-relatednadverse effects limit the use of anti-PD1/PD-L1 antibodies. Here,nwe report the discovery and identification of S4-1, anninnovative small-molecule inhibitor of PD-L1. In vitro, S4-1 effectively altered the PD-L1/PD-1 interaction,ninduced PD-L1 dimerization and internalization, improved its localizationnto endoplasmic reticulum, and thus enhanced the cytotoxicity of peripheralnblood mononuclear cells toward tumor cells. In vivo, S4-1 significantly inhibited tumor growth in bothnlung and colorectal cancer models, particularly in colorectal cancer,nwhere it led to complete clearance of a portion of the tumor cells.nFurthermore, S4-1 induced T-cell activation and inversednthe inhibitory tumor microenvironment, consistent with the PD-L1/PD-1npathway blockade. These data support the continued evaluation of S4-1 as an alternative ICB therapeutic strategy.","PeriodicalId":522541,"journal":{"name":"Figshare","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-12-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147898951","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

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