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

Roberto Butera; Marta Ważyńska; Katarzyna Magiera-Mularz; Jacek Plewka; Bogdan Musielak; Ewa Surmiak; Dominik Sala; Radoslaw Kitel; Marco de Bruyn; Hans W Nijman; Philip H Elsinga; Tad A Holak; Alexander Dömling

doi:10.1021/acsmedchemlett.1c00033

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. eCollection 2021 May 13.

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.

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.