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
  • 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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