2. Academic Validation
  3. Discovery of Orally Potent Small-Molecule CD73 Inhibitor for Cancer Immunotherapy

Discovery of Orally Potent Small-Molecule CD73 Inhibitor for Cancer Immunotherapy

  • J Med Chem. 2025 Jun 12;68(11):11039-11061. doi: 10.1021/acs.jmedchem.5c00035.
Lifang Cen 1,  Weijie Ren 2,  Jiajie Yu 2,  Ming Cheng 2,  Xiangying Kong 2,  Wenxin Yan 1,  Luhua Wang 2,  Xinyue Li 2,  Jing Liu 2,  Zhen Wang 2,  Shiqi Wu 1,  Xiaomeng Sun 2,  Ping Wei 3,  Hongfeng Gu 2,  Qihua Zhu 2,  Yi Zou 2,  Yungen Xu 1 2 4
Affiliations

Affiliations

  • 1 State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 211198, China.
  • 2 Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 211198, China.
  • 3 Hefei Institute of Pharmaceutical Industry Co. Ltd., Hefei 230601, China.
  • 4 Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 211198, China.
PMID: 40409990 DOI: 10.1021/acs.jmedchem.5c00035
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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-176203
    CD73抑制剂
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