发现用于癌症免疫治疗的口服强效小分子 CD73 抑制剂

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 H ,3 H -dihydro-2,4-pyrimidinone moiety was achieved.

Notably, XC-12 exhibited potent in vitro anti-CD73 activity against both soluble and membrane-bound forms (IC 50 = 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.