{"title":"Discovery of Orally Potent Small-Molecule CD73 Inhibitor for Cancer Immunotherapy","authors":"Lifang Cen, Weijie Ren, Jiajie Yu, Ming Cheng, Xiangying Kong, Wenxin Yan, Luhua Wang, Xinyue Li, Jing Liu, Zhen Wang, Shiqi Wu, Xiaomeng Sun, Ping Wei, Hongfeng Gu, Qihua Zhu*, Yi Zou* and Yungen Xu*, ","doi":"10.1021/acs.jmedchem.5c0003510.1021/acs.jmedchem.5c00035","DOIUrl":null,"url":null,"abstract":"<p >CD73, an emerging immune checkpoint, plays a pivotal role in the adenosine (ADO) metabolic pathway by catalyzing the conversion of AMP to ADO. This process has been shown to inhibit the functions of T cells and natural killer (NK) cells, thereby exacerbating the immunosuppressive effects within the tumor microenvironment. These findings underscore the critical role of CD73 in modulating immune cell function and represent a promising therapeutic target for cancer treatment. Herein, a series of novel CD73 inhibitors featuring a 1<i>H</i>,3<i>H</i>-dihydro-2,4-pyrimidinone moiety was achieved. Notably, XC-12 exhibited potent <i>in vitro</i> anti-CD73 activity against both soluble and membrane-bound forms (IC<sub>50</sub> = 12.36 and 1.29 nM, respectively). Furthermore, XC-12 was orally bioavailable and significantly inhibited the tumor growth in the CT26 syngeneic mouse model (TGI: 74%) at a dose of 135 mg/kg. These results suggest that XC-12 may serve as a promising candidate for cancer immunotherapy.</p>","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"68 11","pages":"11039–11061 11039–11061"},"PeriodicalIF":6.8000,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Medicinal Chemistry","FirstCategoryId":"3","ListUrlMain":"https://pubs.acs.org/doi/10.1021/acs.jmedchem.5c00035","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
引用次数: 0
Abstract
CD73, an emerging immune checkpoint, plays a pivotal role in the adenosine (ADO) metabolic pathway by catalyzing the conversion of AMP to ADO. This process has been shown to inhibit the functions of T cells and natural killer (NK) cells, thereby exacerbating the immunosuppressive effects within the tumor microenvironment. These findings underscore the critical role of CD73 in modulating immune cell function and represent a promising therapeutic target for cancer treatment. Herein, a series of novel CD73 inhibitors featuring a 1H,3H-dihydro-2,4-pyrimidinone moiety was achieved. Notably, XC-12 exhibited potent in vitro anti-CD73 activity against both soluble and membrane-bound forms (IC50 = 12.36 and 1.29 nM, respectively). Furthermore, XC-12 was orally bioavailable and significantly inhibited the tumor growth in the CT26 syngeneic mouse model (TGI: 74%) at a dose of 135 mg/kg. These results suggest that XC-12 may serve as a promising candidate for cancer immunotherapy.
期刊介绍：
The Journal of Medicinal Chemistry is a prestigious biweekly peer-reviewed publication that focuses on the multifaceted field of medicinal chemistry. Since its inception in 1959 as the Journal of Medicinal and Pharmaceutical Chemistry, it has evolved to become a cornerstone in the dissemination of research findings related to the design, synthesis, and development of therapeutic agents.
The Journal of Medicinal Chemistry is recognized for its significant impact in the scientific community, as evidenced by its 2022 impact factor of 7.3. This metric reflects the journal's influence and the importance of its content in shaping the future of drug discovery and development. The journal serves as a vital resource for chemists, pharmacologists, and other researchers interested in the molecular mechanisms of drug action and the optimization of therapeutic compounds.
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