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 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.