Discovery of Orally Potent Small-Molecule CD73 Inhibitor for Cancer Immunotherapy
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.
Authors
- Shiqi Wu (ORCID: https://orcid.org/0009-0003-9296-4690)
- Yi Zou (ORCID: https://orcid.org/0000-0001-6782-9380)
- Weijie Ren (ORCID: https://orcid.org/0000-0002-7465-5048)
- Ping Wei (ORCID: https://orcid.org/0000-0003-2953-1609)
- Qihua Zhu (ORCID: https://orcid.org/0000-0003-4314-4226)
- Wenxin Yan (ORCID: https://orcid.org/0000-0003-2725-9840)
- Jiaojiao Yu
- Yungen Xu (ORCID: https://orcid.org/0000-0001-6586-8482)
- Xinyue Li (ORCID: https://orcid.org/0000-0002-7319-6302)
- Jing Liu (ORCID: https://orcid.org/0000-0002-8482-1695)
- Zhen Wang (ORCID: https://orcid.org/0000-0003-4134-1779)
- Ming Cheng (ORCID: https://orcid.org/0000-0002-9495-7983)
- Xiaomeng Sun (ORCID: https://orcid.org/0000-0003-2851-8074)
- Hongfeng Gu (ORCID: https://orcid.org/0009-0004-4385-3430)
- Lifang Cen
- Xiangying Kong (ORCID: https://orcid.org/0000-0003-3769-3368)
- L. Wang
Institutions
- China Pharmaceutical University (CN)
- Hefei Design and Research Institute of Coal Industry (China) (CN)
- State Key Laboratory of Natural Medicine
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-05-23
- DOI
- https://doi.org/10.1021/acs.jmedchem.5c00035
- Primary Topic
- Adenosine and Purinergic Signaling
- Type
- article
- Field-Weighted Citation Impact
- 0.00