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Di-bromo-Based Small-Molecule Inhibitors of the PD-1/PD-L1 Immune Checkpoint
[Image: see text] 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 s...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Chemical
Society
2020
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7584369/ https://www.ncbi.nlm.nih.gov/pubmed/32936638 http://dx.doi.org/10.1021/acs.jmedchem.0c01260 |
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author | Konieczny, Magdalena Musielak, Bogdan Kocik, Justyna Skalniak, Lukasz Sala, Dominik Czub, Miroslawa Magiera-Mularz, Katarzyna Rodriguez, Ismael Myrcha, Maja Stec, Malgorzata Siedlar, Maciej Holak, Tad A. Plewka, Jacek |
author_facet | Konieczny, Magdalena Musielak, Bogdan Kocik, Justyna Skalniak, Lukasz Sala, Dominik Czub, Miroslawa Magiera-Mularz, Katarzyna Rodriguez, Ismael Myrcha, Maja Stec, Malgorzata Siedlar, Maciej Holak, Tad A. Plewka, Jacek |
author_sort | Konieczny, Magdalena |
collection | PubMed |
description | [Image: see text] 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. |
format | Online Article Text |
id | pubmed-7584369 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | American Chemical
Society |
record_format | MEDLINE/PubMed |
spelling | pubmed-75843692020-10-26 Di-bromo-Based Small-Molecule Inhibitors of the PD-1/PD-L1 Immune Checkpoint Konieczny, Magdalena Musielak, Bogdan Kocik, Justyna Skalniak, Lukasz Sala, Dominik Czub, Miroslawa Magiera-Mularz, Katarzyna Rodriguez, Ismael Myrcha, Maja Stec, Malgorzata Siedlar, Maciej Holak, Tad A. Plewka, Jacek J Med Chem [Image: see text] 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. American Chemical Society 2020-09-16 2020-10-08 /pmc/articles/PMC7584369/ /pubmed/32936638 http://dx.doi.org/10.1021/acs.jmedchem.0c01260 Text en This is an open access article published under a Creative Commons Attribution (CC-BY) License (http://pubs.acs.org/page/policy/authorchoice_ccby_termsofuse.html) , which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited. |
spellingShingle | Konieczny, Magdalena Musielak, Bogdan Kocik, Justyna Skalniak, Lukasz Sala, Dominik Czub, Miroslawa Magiera-Mularz, Katarzyna Rodriguez, Ismael Myrcha, Maja Stec, Malgorzata Siedlar, Maciej Holak, Tad A. Plewka, Jacek Di-bromo-Based Small-Molecule Inhibitors of the PD-1/PD-L1 Immune Checkpoint |
title | Di-bromo-Based
Small-Molecule Inhibitors of
the PD-1/PD-L1 Immune Checkpoint |
title_full | Di-bromo-Based
Small-Molecule Inhibitors of
the PD-1/PD-L1 Immune Checkpoint |
title_fullStr | Di-bromo-Based
Small-Molecule Inhibitors of
the PD-1/PD-L1 Immune Checkpoint |
title_full_unstemmed | Di-bromo-Based
Small-Molecule Inhibitors of
the PD-1/PD-L1 Immune Checkpoint |
title_short | Di-bromo-Based
Small-Molecule Inhibitors of
the PD-1/PD-L1 Immune Checkpoint |
title_sort | di-bromo-based
small-molecule inhibitors of
the pd-1/pd-l1 immune checkpoint |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7584369/ https://www.ncbi.nlm.nih.gov/pubmed/32936638 http://dx.doi.org/10.1021/acs.jmedchem.0c01260 |
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