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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(2A)AR) represents an emerging drug target for cancer immunotherapy. The clinical candidate Etrumadenant was developed as an A(2A)AR antagonist with ancillary blockade of the A(2B)AR subtype. It constitutes a unique chemotype featuring a poly-subst...

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Autores principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10235125/
https://www.ncbi.nlm.nih.gov/pubmed/37264098
http://dx.doi.org/10.1038/s42004-023-00894-6
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author 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.
author_facet 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.
author_sort Claff, Tobias
collection PubMed
description The G(s) protein-coupled adenosine A(2A) receptor (A(2A)AR) represents an emerging drug target for cancer immunotherapy. The clinical candidate Etrumadenant was developed as an A(2A)AR antagonist with ancillary blockade of the A(2B)AR 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 A(2A)AR in complex with Etrumadenant, obtained with differently thermostabilized A(2A)AR constructs. This led to the discovery of an unprecedented interaction, a hydrogen bond of T88(3.36) with the cyano group of Etrumadenant. T88(3.36) is mutated in most A(2A)AR constructs used for crystallization, which has prevented the discovery of its interactions. In-vitro characterization of Etrumadenant indicated low selectivity versus the A(1)AR 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 A(2A)AR crystallization construct that is devoid of ligand binding site mutations.
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spelling pubmed-102351252023-06-03 Crystal structure of adenosine A(2A) receptor in complex with clinical candidate Etrumadenant reveals unprecedented antagonist interaction 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. Commun Chem Article The G(s) protein-coupled adenosine A(2A) receptor (A(2A)AR) represents an emerging drug target for cancer immunotherapy. The clinical candidate Etrumadenant was developed as an A(2A)AR antagonist with ancillary blockade of the A(2B)AR 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 A(2A)AR in complex with Etrumadenant, obtained with differently thermostabilized A(2A)AR constructs. This led to the discovery of an unprecedented interaction, a hydrogen bond of T88(3.36) with the cyano group of Etrumadenant. T88(3.36) is mutated in most A(2A)AR constructs used for crystallization, which has prevented the discovery of its interactions. In-vitro characterization of Etrumadenant indicated low selectivity versus the A(1)AR 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 A(2A)AR crystallization construct that is devoid of ligand binding site mutations. Nature Publishing Group UK 2023-06-01 /pmc/articles/PMC10235125/ /pubmed/37264098 http://dx.doi.org/10.1038/s42004-023-00894-6 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
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.
Crystal structure of adenosine A(2A) receptor in complex with clinical candidate Etrumadenant reveals unprecedented antagonist interaction
title Crystal structure of adenosine A(2A) receptor in complex with clinical candidate Etrumadenant reveals unprecedented antagonist interaction
title_full Crystal structure of adenosine A(2A) receptor in complex with clinical candidate Etrumadenant reveals unprecedented antagonist interaction
title_fullStr Crystal structure of adenosine A(2A) receptor in complex with clinical candidate Etrumadenant reveals unprecedented antagonist interaction
title_full_unstemmed Crystal structure of adenosine A(2A) receptor in complex with clinical candidate Etrumadenant reveals unprecedented antagonist interaction
title_short Crystal structure of adenosine A(2A) receptor in complex with clinical candidate Etrumadenant reveals unprecedented antagonist interaction
title_sort crystal structure of adenosine a(2a) receptor in complex with clinical candidate etrumadenant reveals unprecedented antagonist interaction
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10235125/
https://www.ncbi.nlm.nih.gov/pubmed/37264098
http://dx.doi.org/10.1038/s42004-023-00894-6
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