7BEA

Structure of human Programmed cell death 1 ligand 1 (PD-L1) with inhibitor

Summary for 7BEA

• Entry DOI: 10.2210/pdb7bea/pdb
• Descriptor: Programmed cell death 1 ligand 1, 2-(aminomethyl)-6-[(2-methyl-3-phenyl-phenyl)methoxy]-~{N}-(2-phenylethyl)imidazo[1,2-a]pyridin-3-amine (3 entities in total)
• Functional Keywords: pd-l1, immune checkpoint, immune system
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 29820.10

Authors

Magiera-Mularz, K.,Butera, R.,Wazynska, M.,Holak, T.,Domling, A. (deposition date: 2020-12-22, release date: 2021-06-09, Last modification date: 2024-11-13)

Primary citation

Butera, R.,Wazynska, M.,Magiera-Mularz, K.,Plewka, J.,Musielak, B.,Surmiak, E.,Sala, D.,Kitel, R.,de Bruyn, M.,Nijman, H.W.,Elsinga, P.H.,Holak, T.A.,Domling, A.
Design, Synthesis, and Biological Evaluation of Imidazopyridines as PD-1/PD-L1 Antagonists.
Acs Med.Chem.Lett., 12:768-773, 2021

PubMed 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-]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.

PubMed: 34055224
DOI: 10.1021/acsmedchemlett.1c00033

Experimental method

X-RAY DIFFRACTION (2.45 Å)