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bioRxiv · 10.1101/2024.08.05.606339

Discovery of the first-efficacious A2AR negative allosteric modulators for high adenosine cancer immunotherapies

Boujut, M.·Heritier, M.·Gouiller, A.·Suess, C.·Scapozza, A.·De Smedt, T.·Guibert, M.·Tardy, S.·Hamed, H.·Pejoski, D.·Scapozza, L.
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Abstract

Inhibition of adenosine 2A receptor (A2AR) is recognized as a promising immunotherapeutic strategy but is challenged by the ubiquity of A2AR function in the immune system. To develop a safe yet efficacious immunotherapy, the discovery of a novel negative allosteric modulator (NAM) was preferred. Leveraging an in-house, sensitive, high-throughput screening cellular assay, novel A2AR NAM scaffolds were identified followed by an extensive structure-activity relationship (SAR) study, leading to the discovery of potent 2-amino-3,5-dicyanopyridine derivatives. Allosteric mode of action of active compounds was confirmed by shift assay, non-linearity of the Schild plot analysis, biophysical measurements, and retained satisfactory potencies in high-adenosine concentrations. Further correlation of A2AR engagement and downstream signaling was done in a human blood translational assay, clearly showcasing the potential of A2AR allosteric modulation as a novel approach for efficient and safer cancer immunotherapies.

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Boujut, M., Heritier, M., Gouiller, A., Suess, C., Scapozza, A., De Smedt, T., Guibert, M., Tardy, S., Hamed, H., Pejoski, D., Scapozza, L.. 2024-08-07. Discovery of the first-efficacious A2AR negative allosteric modulators for high adenosine cancer immunotherapies. https://doi.org/10.1101/2024.08.05.606339

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