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Kitel, R.* ; Rodríguez, I.* ; del Corte, X.* ; Atmaj, J.* ; Zarnik, M.* ; Surmiak, E.* ; Muszak, D.* ; Magiera-Mularz, K.* ; Popowicz, G.M. ; Holak, T.A.* ; Musielak, B.*

Exploring the surface of the ectodomain of the PD-L1 immune checkpoint with small-molecule fragments.

ACS Chem. Biol. 17, 2655-2663 (2022)
Publ. Version/Full Text Research data DOI PMC
Open Access Gold (Paid Option)
Creative Commons Lizenzvertrag
Development of small molecules targeting the PD-L1/PD-1 interface is advancing both in industry and academia, but only a few have reached early-stage clinical trials. Here, we take a closer look at the general druggability of PD-L1 using in silico hot spot mapping and nuclear magnetic resonance (NMR)-based characterization. We found that the conformational elasticity of the PD-L1 surface strongly influences the formation of hot spots. We deconstructed several generations of known inhibitors into fragments and examined their binding properties using differential scanning fluorimetry (DSF) and protein-based nuclear magnetic resonance (NMR). These biophysical analyses showed that not all fragments bind to the PD-L1 ectodomain despite having the biphenyl scaffold. Although most of the binding fragments induced PD-L1 oligomerization, two compounds, TAH35 and TAH36, retain the monomeric state of proteins upon binding. Additionally, the presence of the entire ectodomain did not affect the binding of the hit compounds and dimerization of PD-L1. The data demonstrated here provide important information on the PD-L1 druggability and the structure-activity relationship of the biphenyl core moiety and therefore may aid in the design of novel inhibitors and focused fragment libraries for PD-L1.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Medicinal Chemistry Publications; Protein-protein Interactions; Hot-spots; Ligand; Inhibitors; Impact
ISSN (print) / ISBN 1554-8929
e-ISSN 1554-8937
Journal ACS Chemical Biology
Quellenangaben Volume: 17, Issue: 9, Pages: 2655-2663 Article Number: , Supplement: ,
Publisher American Chemical Society (ACS)
Publishing Place Washington
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Structural Biology (STB)
Grants Narodowym Centrum Nauki