Inhibition of CD39 as a potential strategy for immunotherapy
2022
University of Bonn, Bonn, Germany
An important mechanism, by which cancer cells achieve immune escape, is the release of extracellular adenosine into their microenvironment. The ectonucleotidases CD39 and CD73 play an essential role in this process. Inhibition of CD39 is thus expected to be an effective strategy for the (immuno)therapy of cancer. However, suitable small-molecule inhibitors for CD39 are not available. Here, the researchers pursued a repurposing approach by screening a self-compiled collection of approved, mostly ATP-competitive protein kinase inhibitors, on human CD39. The best hit compound was further characterized and evaluated in various orthogonal assays and enzyme preparations and on human immune and cancer cells. The tyrosine kinase inhibitor ceritinib, a potent anticancer drug, was found to strongly inhibit CD39 showing selectivity versus other ectonucleotidases. This discovery will provide the basis (i) to develop more potent and balanced dual CD39/ALK inhibitors, and (ii) to optimize the ceritinib scaffold towards interaction with CD39 to obtain potent and selective drug-like CD39 inhibitors for future studies.
Protein kinase inhibitor ceritinib blocks ectonucleotidase CD39 – a promising target for cancer immunotherapy
Christa E. Müller
Added on: 10-25-2022
[1] https://jitc.bmj.com/content/10/8/e004660[2] https://www.drugtargetreview.com/news/104773/researchers-find-cd39-inhibition-could-be-an-effective-strategy-for-immunotherapy/?utm_source=Email+marketing&utm_medium=email&utm_campaign=DTR+-+Industry+Insight+-+Bio+IVT+-+Immuno-oncology+-+09.09.22&utm_term=Researchers+develop+a+small+molecule+that+makes+immunotherapy+available+to+all+cancer+patients&utm_content=https%3a%2f%2femails.drugtargetreview.com%2frussellpublishinglz%2f&gator_td=5XClbgWfLEdipSqm%2bx7T6xcOrwZXFd5HHf%2fL%2feRG%2f55t27jmFadcdE86RpuNbRy5HiTrTnDc%2fD6%2fUBkjtGb%2fRFRupVCI4SBO5uCTEIySmIQyxk36imcqtwbZBLfKmo69WMkmwbfNuobHKAk4VVCsAQ98Wlbqh2CZUK7Nn0lp%2fQTvJ0JJ%2f%2foAYGIXUcRKkik3B14olGYMeaFbWAkp7%2bitbYJIjJfNYGPlOnBom042B9KQqd00h4n%2f6U2%2bzQO%2bTHQU
