Development of potent inhibitors to boost the immune system's ability to fight cancer

One breakthrough in cancer therapy has been immune checkpoint inhibitors (ICIs), drugs that reactivate immune T cells and help them fight tumors again. However, only about 20–50% of patients respond well to this treatment. Researchers are therefore seeking alternative therapeutic strategies. A small and well-known molecule called adenosine plays a key role in these efforts.

When tumor cells are stressed or dying, they release ATP, which is normally a signal that something is wrong in the tissue. But in the tumor microenvironment, ATP gets rapidly broken down by two enzymes, CD39 and CD73. Released adenosine acts like a chemical “calm-down” signal, binds to immune cells (T cells, NK cells, and others), and tells them to slow down, reducing their ability to kill cancer cells. Targeting CD73 therefore represents a promising strategy for developing new cancer treatments.

At IOCB Prague, interdisciplinary teams led by Jan Řezáč, Jan Konvalinka, and Michal Hocek used a newly developed high-throughput screening method to test over 5,000 compounds, identifying two ribonucleoside derivatives as promising CD73 inhibitors. The scientists then improved the compounds’ activity by carefully modifying the ribonucleoside scaffold with bulky (het)aryl groups. Further optimization improved the pharmacokinetic properties of these compounds, yielding inhibitors with low clearance, long half-life, high solubility, and strong selectivity over related enzymes such as CD39. In cellular experiments, the compounds reduced adenosine production in cancer cells, restored T cell activation, and showed no toxicity toward human fibroblasts. The most active compound showed a single-digit picomolar inhibition constant (Ki).

These findings establish a strong foundation for further in vivo efficacy and combination studies, which will explore the therapeutic potential of this novel inhibitor class.

• Šinkevičiūtė, U.; Šímová, M.; Staník, R.; Poštová Slavětínská, L.; Blažková, K.; Šácha, P.; Lepšík, M.; Řezáč, J.; Konvalinka, J.; Ormsby, T.; Tichý, M.; Hocek, M. Potent Competitive Inhibitors of Ecto-5′-Nucleotidase (CD73) Based on 6-(Het)aryl-7-deazapurine Ribonucleoside 5′-O-Bisphosphonates. ACS Pharmacol. Transl. Sci. 2026, 9 (1), 191–213. https://doi.org/10.1021/acsptsci.5c00707