Related Experiment Video
Updated: Jun 13, 2025
Identifying PD-1/PD-L1 Inhibitors with Surface Plasmon Resonance Technology
Published on: May 2, 2025
Discovery of Orally Potent Small-Molecule CD73 Inhibitor for Cancer Immunotherapy
Lifang Cen1, Weijie Ren2, Jiajie Yu2
1State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 211198, China.
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.
Insights
A novel CD73 inhibitor, XC-12, shows potent activity against cancer by blocking adenosine production. This compound demonstrated significant tumor growth inhibition in preclinical models, suggesting its potential for cancer immunotherapy.
Area of Science:
- Immunology
- Biochemistry
- Pharmacology
Background:
- CD73 is an immune checkpoint enzyme crucial in the adenosine metabolic pathway.
- CD73 activity promotes an immunosuppressive tumor microenvironment by inhibiting T cell and NK cell function.
- Targeting CD73 presents a promising strategy for cancer immunotherapy.
Purpose of the Study:
- To synthesize and evaluate novel CD73 inhibitors.
- To assess the efficacy of a lead compound, XC-12, in preclinical cancer models.
Main Methods:
- Synthesis of novel compounds featuring a 1H,3H-dihydro-2,4-pyrimidinone moiety.
- In vitro evaluation of anti-CD73 activity against soluble and membrane-bound forms.
- Assessment of oral bioavailability and in vivo anti-tumor efficacy in a CT26 syngeneic mouse model.
Main Results:
- XC-12 demonstrated potent in vitro inhibition of CD73 with low nanomolar IC50 values.
- XC-12 was found to be orally bioavailable.
- XC-12 significantly inhibited tumor growth in the CT26 model, achieving 74% tumor growth inhibition at 135 mg/kg.
Conclusions:
- The novel CD73 inhibitors, particularly XC-12, are effective in blocking CD73 activity.
- XC-12 exhibits promising anti-tumor efficacy and oral bioavailability, supporting its potential as a cancer immunotherapy agent.
More Related Videos
07:43Using 22C3 Anti-PD-L1 Antibody Concentrate on Biopsy and Cytology Samples from Non-small Cell Lung Cancer Patients
Published on: September 25, 2018
08:46A Real-time Potency Assay for Chimeric Antigen Receptor T Cells Targeting Solid and Hematological Cancer Cells
Published on: November 12, 2019
