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Publication Abstract from PubMed

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-Bienayme 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.

Design, Synthesis, and Biological Evaluation of Imidazopyridines as PD-1/PD-L1 Antagonists.,Butera R, Wazynska M, Magiera-Mularz K, Plewka J, Musielak B, Surmiak E, Sala D, Kitel R, de Bruyn M, Nijman HW, Elsinga PH, Holak TA, Domling A ACS Med Chem Lett. 2021 Apr 28;12(5):768-773. doi:, 10.1021/acsmedchemlett.1c00033. eCollection 2021 May 13. PMID:34055224^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.