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.

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.