化学
癌症免疫疗法
癌症
免疫疗法
小分子
口服活性
药理学
立体化学
生物化学
体外
内科学
医学
作者
Lifang Cen,Weijie Ren,Jiaojiao Yu,Ming Cheng,Xiangying Kong,Wenxin Yan,L. Wang,Xinyue Li,Jing Liu,Zhen Wang,Shiqi Wu,Xiaomeng Sun,Ping Wei,Hongfeng Gu,Qihua Zhu,Yi Zou,Yungen Xu
标识
DOI:10.1021/acs.jmedchem.5c00035
摘要
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.
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