Discovery of the First Efficacious Adenosine 2A Receptor Negative Allosteric Modulators for High Adenosine Cancer Immunotherapies

  • J Med Chem. 2025 Feb 27;68(4):4059-4078. doi: 10.1021/acs.jmedchem.4c01691.
Margot Boujut  1  2 ,  Margaux Héritier  1  2 ,  Aurélie Gouiller  1  2 ,  Camille Süess  1  2 ,  Alessandro Scapozza  1 ,  Thibaut De Smedt  1 ,  Maxime Guibert  1 ,  Sébastien Tardy  1  2 ,  Hesham M Ismail  1  2  3 ,  David Pejoski  1  2  3 ,  Leonardo Scapozza  1  2  3
Affiliations
  • 1. School of Pharmaceutical Sciences, University of Geneva, 1206 Geneva, Switzerland.
  • 2. Institute of Pharmaceutical Sciences of Western Switzerland, University of Geneva, 1206 Geneva, Switzerland.
  • 3. Adoram Therapeutics, 1212 Grand-Lancy, Switzerland.
PMID: 39855635 DOI: 10.1021/acs.jmedchem.4c01691
Abstract

Inhibition of the 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. The allosteric mode of action of active compounds was confirmed by progressive fold-shift assay, nonlinearity 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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