Journal of Medicinal Chemistry· 2026Q1
Discovery of LB10, a Potent and Orally Bioavailable Inhibitor of Ecto-5′-Nucleotidase as a Single Agent or in Combination for the Treatment of Lung Cancer
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- Q1SCImago
- 2026year
Short summary
LB10, a novel aryl alkyl ether-based inhibitor of ecto-5′-nucleotidase (CD73), potently inhibits tumor growth in mice, showing promise as a single agent or in combination therapy for lung cancer.
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Key points
- LB10 is a potent, orally bioavailable inhibitor of ecto-5′-nucleotidase (CD73) with IC50 values of 8.1 nM (biochemical) and 2.7 nM (cell-based).
- Enzyme kinetic and co-crystallization studies confirmed LB10 acts as a competitive inhibitor.
- LB10 showed no significant cytotoxicity and favorable pharmacokinetic properties.
- Oral administration of LB10 inhibited tumor growth in a syngeneic Lewis lung carcinoma mouse model.
- LB10 demonstrated synergistic effects when combined with paclitaxel or an anti-PD-1 antibody, mediated by immune activation.
AI-generated from the title and abstract; the full text is not read.
Abstract
Abstract Ecto-5-nucleotidase (CD73), a rate-limiting enzyme in the adenosine pathway, plays a crucial role in mediating tumor immunosuppression and has emerged as an attractive target for cancer immunotherapy. A series of aryl alkyl ether-based CD73 inhibitors were designed and synthesized. Compound LB10 stood out as the most promising inhibitor from this series, with IC50 values of 8.1 nM and 2.7 nM in biochemical and cell-based assays, respectively. This compound was confirmed to be a competitive inhibitor by enzyme kinetic and co-crystallization experiments. The compound exhibited no apparent cytotoxicity and a favorable pharmacokinetic profile. In a syngeneic Lewis lung carcinoma mouse model, oral administration of LB10 significantly inhibited tumor growth and synergized with paclitaxel or an anti-PD-1 antibody via immune activation. Collectively, these results establish LB10 as a promising CD73 inhibitor warranting further development.
The authors' abstract, as published at the source. Journal of Medicinal Chemistry, 2026 · DOI ↗
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