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Design, Synthesis, and Biological Evaluation of Imidazopyridines as PD-1/PD-L1 Antagonists

[Image: see text] The PD-1/PD-L1 axis has proven to be a highly efficacious target for cancer immune checkpoint therapy with several approved antibodies. Also, small molecules based on a biphenyl core can antagonize PD-1/PD-L1, leading to the in vitro formation of PD-L1 dimers. However, their develo...

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Autores principales: Butera, Roberto, Ważyńska, Marta, Magiera-Mularz, Katarzyna, Plewka, Jacek, Musielak, Bogdan, Surmiak, Ewa, Sala, Dominik, Kitel, Radoslaw, de Bruyn, Marco, Nijman, Hans W., Elsinga, Philip H., Holak, Tad A., Dömling, Alexander
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2021
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8155249/
https://www.ncbi.nlm.nih.gov/pubmed/34055224
http://dx.doi.org/10.1021/acsmedchemlett.1c00033
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author Butera, Roberto
Ważyńska, Marta
Magiera-Mularz, Katarzyna
Plewka, Jacek
Musielak, Bogdan
Surmiak, Ewa
Sala, Dominik
Kitel, Radoslaw
de Bruyn, Marco
Nijman, Hans W.
Elsinga, Philip H.
Holak, Tad A.
Dömling, Alexander
author_facet Butera, Roberto
Ważyńska, Marta
Magiera-Mularz, Katarzyna
Plewka, Jacek
Musielak, Bogdan
Surmiak, Ewa
Sala, Dominik
Kitel, Radoslaw
de Bruyn, Marco
Nijman, Hans W.
Elsinga, Philip H.
Holak, Tad A.
Dömling, Alexander
author_sort Butera, Roberto
collection PubMed
description [Image: see text] The PD-1/PD-L1 axis has proven to be a highly efficacious target for cancer immune checkpoint therapy with several approved antibodies. Also, small molecules based on a biphenyl core can antagonize PD-1/PD-L1, leading to the in vitro formation of PD-L1 dimers. However, their development remains challenging, as we do not yet fully understand their mode of action. In this work, we designed a new scaffold based on our previously solved high-resolution structures of low-molecular-weight inhibitors bound to PD-L1. A small compound library was synthesized using the Groebke–Blackburn–Bienaymé multicomponent reaction (GBB-3CR), resulting in the structure–activity relationship of imidazo[1,2-a]pyridine-based inhibitors. These inhibitors were tested for their biological activity using various biophysical assays giving potent candidates with low-micromolar PD-L1 affinities. An obtained PD-L1 cocrystal structure reveals the binding to PD-L1. Our results open the door to an interesting bioactive scaffold that could lead to a new class of PD-L1 antagonists.
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spelling pubmed-81552492021-05-28 Design, Synthesis, and Biological Evaluation of Imidazopyridines as PD-1/PD-L1 Antagonists Butera, Roberto Ważyńska, Marta Magiera-Mularz, Katarzyna Plewka, Jacek Musielak, Bogdan Surmiak, Ewa Sala, Dominik Kitel, Radoslaw de Bruyn, Marco Nijman, Hans W. Elsinga, Philip H. Holak, Tad A. Dömling, Alexander ACS Med Chem Lett [Image: see text] The PD-1/PD-L1 axis has proven to be a highly efficacious target for cancer immune checkpoint therapy with several approved antibodies. Also, small molecules based on a biphenyl core can antagonize PD-1/PD-L1, leading to the in vitro formation of PD-L1 dimers. However, their development remains challenging, as we do not yet fully understand their mode of action. In this work, we designed a new scaffold based on our previously solved high-resolution structures of low-molecular-weight inhibitors bound to PD-L1. A small compound library was synthesized using the Groebke–Blackburn–Bienaymé multicomponent reaction (GBB-3CR), resulting in the structure–activity relationship of imidazo[1,2-a]pyridine-based inhibitors. These inhibitors were tested for their biological activity using various biophysical assays giving potent candidates with low-micromolar PD-L1 affinities. An obtained PD-L1 cocrystal structure reveals the binding to PD-L1. Our results open the door to an interesting bioactive scaffold that could lead to a new class of PD-L1 antagonists. American Chemical Society 2021-04-28 /pmc/articles/PMC8155249/ /pubmed/34055224 http://dx.doi.org/10.1021/acsmedchemlett.1c00033 Text en © 2021 The Authors. Published by American Chemical Society Permits non-commercial access and re-use, provided that author attribution and integrity are maintained; but does not permit creation of adaptations or other derivative works (https://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Butera, Roberto
Ważyńska, Marta
Magiera-Mularz, Katarzyna
Plewka, Jacek
Musielak, Bogdan
Surmiak, Ewa
Sala, Dominik
Kitel, Radoslaw
de Bruyn, Marco
Nijman, Hans W.
Elsinga, Philip H.
Holak, Tad A.
Dömling, Alexander
Design, Synthesis, and Biological Evaluation of Imidazopyridines as PD-1/PD-L1 Antagonists
title Design, Synthesis, and Biological Evaluation of Imidazopyridines as PD-1/PD-L1 Antagonists
title_full Design, Synthesis, and Biological Evaluation of Imidazopyridines as PD-1/PD-L1 Antagonists
title_fullStr Design, Synthesis, and Biological Evaluation of Imidazopyridines as PD-1/PD-L1 Antagonists
title_full_unstemmed Design, Synthesis, and Biological Evaluation of Imidazopyridines as PD-1/PD-L1 Antagonists
title_short Design, Synthesis, and Biological Evaluation of Imidazopyridines as PD-1/PD-L1 Antagonists
title_sort design, synthesis, and biological evaluation of imidazopyridines as pd-1/pd-l1 antagonists
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8155249/
https://www.ncbi.nlm.nih.gov/pubmed/34055224
http://dx.doi.org/10.1021/acsmedchemlett.1c00033
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