Discovery and optimization of betulinic acid derivatives as novel potent CD73 inhibitors
Yanming Zhang1, Shuang Ye2, Yuan Wang3
1School of Pharmacy, The Second Military Medical University, 325 Guohe Road, Shanghai 200433, People's Republic of China.
Abstract:
The vast research and clinical result have verified the success of cancer immunotherapy. However, there is also facing the enormous challenges such as lack of precise pre-clinical models, optimal combined therapy regimen and acquired resistance to immunotherapy. Adenosine is a potent immune-modulating molecule and overexpression of CD73 on tumor leads to the high concentration of adenosine. Blockade of the key adenosine-generating enzyme CD73 can be a promising strategy for cancer immunotherapy. Here, we report the discovery of betulinic acid as a novel CD73 inhibitor lead compound by a hit-based substructure search strategy. Subsequent optimization led to the discovery of betulinic acid carbamate derivative ZM514 with 5.2-fold increased potency compared to lead compound. Simultaneously, study has showed that compound ZM514 was not a cytotoxic agent while betulinic acid showed modest antiproliferative activity. The present result provides a valuable inhibitor against the promising immuno-oncology target for further development.
Insights
Researchers discovered betulinic acid as a novel CD73 inhibitor for cancer immunotherapy. Its derivative, ZM514, shows increased potency and is a promising immuno-oncology target.
Area of Science:
- Oncology
- Immunology
- Medicinal Chemistry
Background:
- Cancer immunotherapy has shown success but faces challenges like resistance and lack of precise models.
- Adenosine, a potent immune modulator, is linked to cancer progression via CD73 overexpression.
- Targeting CD73, an enzyme generating adenosine, presents a promising cancer immunotherapy strategy.
Purpose of the Study:
- To identify novel inhibitors of the CD73 enzyme.
- To develop potent compounds for cancer immunotherapy by targeting adenosine production.
Main Methods:
- Hit-based substructure search was employed to discover lead compounds.
- Chemical optimization of lead compounds was performed.
- In vitro assays were used to evaluate compound potency and cytotoxicity.
Main Results:
- Betulinic acid was identified as a novel CD73 inhibitor lead compound.
- A betulinic acid carbamate derivative, ZM514, demonstrated a 5.2-fold increase in potency over the lead compound.
- ZM514 exhibited no cytotoxic effects, while betulinic acid showed modest antiproliferative activity.
Conclusions:
- Betulinic acid and its derivative ZM514 are effective CD73 inhibitors.
- ZM514 represents a valuable, non-cytotoxic inhibitor for the immuno-oncology target CD73.
- These findings support further development of CD73 inhibitors for cancer treatment.
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