2. Academic Validation
  3. Crystal structure of adenosine A2A receptor in complex with clinical candidate Etrumadenant reveals unprecedented antagonist interaction

Crystal structure of adenosine A2A receptor in complex with clinical candidate Etrumadenant reveals unprecedented antagonist interaction

  • Commun Chem. 2023 Jun 1;6(1):106. doi: 10.1038/s42004-023-00894-6.
Tobias Claff 1,  Jonathan G Schlegel 2,  Jan H Voss 2,  Victoria J Vaaßen 2,  Renato H Weiße 3,  Robert K Y Cheng 4,  Sandra Markovic-Mueller 4,  Denis Bucher 4,  Norbert Sträter 3,  Christa E Müller 5
Affiliations

Affiliations

  • 1 PharmaCenter Bonn & Pharmaceutical Institute, Department of Pharmaceutical & Medicinal Chemistry, University of Bonn, An der Immenburg 4, 53113, Bonn, Germany. tobias.claff@uni-bonn.de.
  • 2 PharmaCenter Bonn & Pharmaceutical Institute, Department of Pharmaceutical & Medicinal Chemistry, University of Bonn, An der Immenburg 4, 53113, Bonn, Germany.
  • 3 Institute of Bioanalytical Chemistry, Center for Biotechnology and Biomedicine, University of Leipzig, Deutscher Platz 5, 04103, Leipzig, Germany.
  • 4 leadXpro AG, PARK InnovAARE, 5234, Villigen, Switzerland.
  • 5 PharmaCenter Bonn & Pharmaceutical Institute, Department of Pharmaceutical & Medicinal Chemistry, University of Bonn, An der Immenburg 4, 53113, Bonn, Germany. christa.mueller@uni-bonn.de.
PMID: 37264098 DOI: 10.1038/s42004-023-00894-6
Abstract

The Gs protein-coupled adenosine A2A receptor (A2AAR) represents an emerging drug target for Cancer Immunotherapy. The clinical candidate Etrumadenant was developed as an A2AAR antagonist with ancillary blockade of the A2BAR subtype. It constitutes a unique chemotype featuring a poly-substituted 2-amino-4-phenyl-6-triazolylpyrimidine core structure. Herein, we report two crystal structures of the A2AAR in complex with Etrumadenant, obtained with differently thermostabilized A2AAR constructs. This led to the discovery of an unprecedented interaction, a hydrogen bond of T883.36 with the cyano group of Etrumadenant. T883.36 is mutated in most A2AAR constructs used for crystallization, which has prevented the discovery of its interactions. In-vitro characterization of Etrumadenant indicated low selectivity versus the A1AR subtype, which can be rationalized by the structural data. These results will facilitate the future design of AR antagonists with desired selectivity. Moreover, they highlight the advantages of the employed A2AAR crystallization construct that is devoid of ligand binding site mutations.

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