OP-5244 is a Potent and Orally Bioavailable CD73 Inhibitor

CD73, also known as 5′-nucleotidase (5′-NT), is commonly used to convert amp to adenosine. Specifically, CD73 is a surface enzyme in multiple cells. The enzyme mediates autocrine and paracrine danger signals of ATP and ADP to hydrolyze into anti-inflammatory adenosine. Besides, Adenosine pathway mediated immunosuppression is very important for maintaining the immune system homeostasis. Moreover, CD73 is a glycosylphosphatidylinositol (GPI)- anchored cell surface protein that phosphorylates extracellular amp to form adenosine (ADO). The immunosuppressive function of T regulatory cells also depends on the expression of CD73. Extracellular 5-nucleotidase CD73 has a unique function of regulating the production of immunosuppressive ADO through AMP hydrolysis. Furthermore,  overexpression of CD73 is in many cancers, leading to increased levels of ADO. Therefore, it is a potential strategy to reduce the level of ADO by inhibiting CD73. OP-5244 is a potent and orally bioavailable inhibitor of CD73.

OP-5244 is a potent and orally bioavailable CD73 inhibitor.

How does OP-5244 work on the target? Let’s study it together. First of all, OP-5244 is a potent and orally bioavailable inhibitor of CD73, with an IC50 of 0.25 nM. Meanwhile, OP-5244 reverses immunosuppression through the blocking of adenosine production and has the potential for cancer research.

In the second place, OP-5244 inhibits the production of ADO, with an EC50 of 0.79 nM in H1568 (NSCLC) cells. Nonetheless, OP-5244 inhibits AMP hydrolysis to ADO in peripheral blood-derived CD8+ T cells with an EC50 of 0.22 nM. Importantly, OP-5244 rescues AMP-suppressed CD8+ T cells proliferation and cytokine production with 4.1-1000 nM in 96 h. Particularly, OP-5244  inhibits ADO production completely in human and murine cancer cell lines (H1568 and EMT6, respectively) with 0.01 nM-10 μM.

Last but not the least, OP-5244, with 15 mg/kg/day by s.c. for 13 days, exhibits anti-tumor effects as a single agent as shown by the tumor growth inhibition in mice. Obviously, OP-5244, with 150 mg/kg by p.o. twice daily for 16 days, increases CD8+ T cells infiltration, and reverses immunosuppression in mice. OP-5244 exhibits terminal elimination half-lives due to moderate plasma clearance and low steady-state volume of distribution.

All in all, OP-5244 is a potent and orally bioavailable CD73 inhibitor with anti-tumor effects.


Du X, et, al. Med Chem. 2020 Sep 24;63(18):10433-10459.