Crystal structure of adenosine A_2A receptor in complex with clinical candidate Etrumadenant reveals unprecedented antagonist interaction

The G_s protein-coupled adenosine A_2A receptor (A_2AAR) is an emerging drug target for cancer immunotherapy. The clinical candidate Etrumadenant, a unique chemotype with a poly-substituted 2-amino-4-phenyl-6-triazolylpyrimidine core, acts as an A_2AAR antagonist with A_2BAR blockade. This study presents two crystal structures of A_2AAR bound to Etrumadenant, revealing an unprecedented hydrogen bond between T88^3.36 and the cyano group of Etrumadenant. This interaction, previously unobserved due to mutations in most A_2AAR constructs used for crystallization, is discussed along with in-vitro data showing low selectivity versus the A₁AR. The findings facilitate future AR antagonist design.

Tobias Claff, Jonathan G. Schlegel, Jan H. Voss, Victoria J. Vaaßen, Renato H. Weiße, Robert K. Y. Cheng, Sandra Markovic-Mueller, Denis Bucher, Norbert Sträter, Christa E. Müller