The adenosinergic pathway represents an attractive new therapeutic approach in cancer immunotherapy. In this pathway, ecto-5-nucleotidase CD73 has the unique function of regulating production of immunosuppressive adenosine (ADO) through the hydrolysis of AMP. CD73 is overexpressed in many cancers, resulting in elevated levels of ADO that correspond to poor patient prognosis. Therefore, reducing the level of ADO via inhibition of CD73 is a potential strategy for treating cancers. Based on the binding mode of adenosine 5′-(α,β-methylene)diphosphate (AOPCP) with human CD73, we designed a series of novel monophosphonate small-molecule CD73 inhibitors. Among them, OP-5244 (35) proved to be a highly potent and orally bioavailable CD73 inhibitor. In preclinical studies, 35 completely inhibited ADO production in both human cancer cells and CD8⁺ T cells. Furthermore, 35 lowered the ratio of ADO/AMP significantly and reversed immunosuppression in mouse models, indicating its potential as an in vivo tool compound for further development.

中文翻译：

---

口服生物可利用的小分子CD73抑制剂（OP-5244）通过阻断腺苷的产生来逆转免疫抑制。

腺苷能途径代表了癌症免疫疗法中一种有吸引力的新治疗方法。在此途径中，ecto-5-核苷酸酶CD73具有通过AMP水解调节免疫抑制腺苷（ADO）产生的独特功能。CD73在许多癌症中过表达，导致ADO水平升高，这与患者预后不良相对应。因此，通过抑制CD73降低ADO水平是治疗癌症的潜在策略。基于腺苷5'-（α，β-亚甲基）二磷酸腺苷（AOPCP）与人CD73的结合方式，我们设计了一系列新型单膦酸酯小分子CD73抑制剂。其中，OP-5244（35）被证明是一种高效且可口服生物利用的CD73抑制剂。在临床前研究中，35完全抑制人癌细胞和CD8 ⁺ T细胞中ADO的产生。此外，35在小鼠模型中显着降低了ADO / AMP的比例并逆转了免疫抑制作用，表明其作为进一步开发的体内工具化合物的潜力。