Di-bromo-Based Small-Molecule Inhibitors of the PD-1/PD-L1 Immune Checkpoint
| Autor: | Maciej Siedlar, Lukasz Skalniak, Ismael Rodríguez, Dominik Sala, Tad A. Holak, Magdalena Konieczny, Jacek Plewka, Justyna Kocik, Małgorzata Stec, Katarzyna Magiera-Mularz, Miroslawa Czub, Maja Myrcha, Bogdan Musielak |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
medicine.drug_class
medicine.medical_treatment Proton Magnetic Resonance Spectroscopy Programmed Cell Death 1 Receptor Monoclonal antibody 01 natural sciences Jurkat cells Article B7-H1 Antigen Small Molecule Libraries 03 medical and health sciences Jurkat Cells Cancer immunotherapy PD-L1 Drug Discovery medicine Humans 030304 developmental biology 0303 health sciences biology Chemistry Immunotherapy Bromine Small molecule Immune checkpoint 0104 chemical sciences 010404 medicinal & biomolecular chemistry Cancer research biology.protein Molecular Medicine Antibody |
| Zdroj: | Journal of Medicinal Chemistry |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | Immune checkpoint blockade is one of the most promising strategies of cancer immunotherapy. However, unlike classical targeted therapies, it is currently solely based on expensive monoclonal antibodies, which often inflict immune-related adverse events. Herein, we propose a novel small-molecule inhibitor targeted at the most clinically relevant immune checkpoint, PD-1/PD-L1. The compound is capable of disrupting the PD-1/PD-L1 complex by antagonizing PD-L1 and, therefore, restores activation of T cells similarly to the antibodies, while being cheap in production and possibly nonimmunogenic. The final compound is significantly smaller than others reported in the literature while being nontoxic to cells even at high concentrations. The scaffold was designed using a structure-activity relationship screening cascade based on a new antagonist-induced dissociation NMR assay, called the weak-AIDA-NMR. Weak-AIDA-NMR finds true inhibitors, as opposed to only binders to the target protein, in early steps of lead compound development, and this process makes it less time and cost consuming. |
| Databáze: | OpenAIRE |
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