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

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 1,3-dihydro-2,4-pyrimidinone moiety was achieved. Notably, XC-12 exhibited potent anti-CD73 activity against both soluble and membrane-bound forms (IC = 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.