| Autor: |
Claff, Tobias, Schlegel, Jonathan G., Voss, Jan H., Vaaßen, Victoria J., Weiße, Renato H., Cheng, Robert K. Y., Markovic-Mueller, Sandra, Bucher, Denis, Sträter, Norbert, Müller, Christa E. |
| Předmět: |
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| Zdroj: |
Communications Chemistry; 6/1/2023, Vol. 6 Issue 1, p1-10, 10p |
| Abstrakt: |
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. Etrumadenant has been developed as a dual-acting adenosine A2A/A2B receptor antagonist, and is now in clinical trials for the treatment of cancer, however, the exact drug–receptor binding mode is unknown. Here, the authors determine the high-resolution co-crystal structure of Etrumadenant with a thermostabilized A2AAR construct and reveal the interaction of its cyano group with T883.36. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
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