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

2021; American Chemical Society; Volume: 12; Issue: 5 Linguagem: Inglês

10.1021/acsmedchemlett.1c00033

1948-5875

Roberto Butera, Marta A. Ważyńska, Katarzyna Magiera‐Mularz, Jacek Plewka, Bogdan Musielak, Ewa Surmiak, Dominik Sala, Radosław Kitel, Marco de Bruyn, Hans W. Nijman, Philip H. Elsinga, Tad A. Holak, Alexander Dömlingꝉ,

Click Chemistry and Applications

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.