2. Academic Validation
  3. Design, Synthesis, and Biological Evaluation of Imidazopyridines as PD-1/PD-L1 Antagonists

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

  • ACS Med Chem Lett. 2021 Apr 28;12(5):768-773. doi: 10.1021/acsmedchemlett.1c00033.
Roberto Butera 1,  Marta Ważyńska 2,  Katarzyna Magiera-Mularz 3,  Jacek Plewka 3,  Bogdan Musielak 3,  Ewa Surmiak 3,  Dominik Sala 3,  Radoslaw Kitel 3,  Marco de Bruyn 2,  Hans W Nijman 2,  Philip H Elsinga 4,  Tad A Holak 3,  Alexander Dömling 1
Affiliations

Affiliations

  • 1 Department of Drug Design, University of Groningen, A. Deusinglaan 1, 9713 AV Groningen, The Netherlands.
  • 2 Department of Obstetrics and Gynaecology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands.
  • 3 Department of Crystal Chemistry and Crystal Physics Faculty of Chemistry, Jagiellonian University, Gronostajowa 2, 30-387 Kraków, Poland.
  • 4 Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands.
PMID: 34055224 DOI: 10.1021/acsmedchemlett.1c00033
Abstract

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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