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Turning a Tumor Microenvironment Pitfall into Opportunity: Discovery of Benzamidoxime as PD-L1 Ligand with pH-Dependent Potency
PD-1/PD-L1 protein complex is attracting a great deal of interest as a drug target for the design of immune therapies able to block its assembly. Although some biologic drugs have entered clinical use, their poor response rate in patients are demanding further efforts to design small molecule inhibi...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10054428/ https://www.ncbi.nlm.nih.gov/pubmed/36982608 http://dx.doi.org/10.3390/ijms24065535 |
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author | Bianconi, Elisa Riccio, Alessandra Ruta, Luana Bigiotti, Carlo Carotti, Andrea Moretti, Sonia Cerra, Bruno Gioiello, Antimo Ferlin, Simone Puxeddu, Efisio Macchiarulo, Antonio |
author_facet | Bianconi, Elisa Riccio, Alessandra Ruta, Luana Bigiotti, Carlo Carotti, Andrea Moretti, Sonia Cerra, Bruno Gioiello, Antimo Ferlin, Simone Puxeddu, Efisio Macchiarulo, Antonio |
author_sort | Bianconi, Elisa |
collection | PubMed |
description | PD-1/PD-L1 protein complex is attracting a great deal of interest as a drug target for the design of immune therapies able to block its assembly. Although some biologic drugs have entered clinical use, their poor response rate in patients are demanding further efforts to design small molecule inhibitors of PD-1/PD-L1 complex with higher efficacy and optimal physicochemical properties. Dysregulation of pH in the tumor microenvironment is indeed one of the key mechanisms promoting drug resistance and lack of response in cancer therapy. Integrating computational and biophysical approaches, herein we report a screening campaign that has led to identifying VIS310 as a novel ligand of PD-L1, with physicochemical properties enabling a pH-dependent binding potency. Additional optimization efforts by analogue-based screening have been instrumental to disclosing VIS1201, which exhibits improved binding potency against PD-L1 and is able to inhibit PD-1/PD-L1 complex formation in a ligand binding displacement assay. While providing preliminary structure–activity relationships (SARs) of a novel class of PD-L1 ligands, our results lay the foundation for the discovery of immunoregulatory small molecules resilient to tumor microenvironmental conditions for escaping drug-resistance mechanisms. |
format | Online Article Text |
id | pubmed-10054428 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-100544282023-03-30 Turning a Tumor Microenvironment Pitfall into Opportunity: Discovery of Benzamidoxime as PD-L1 Ligand with pH-Dependent Potency Bianconi, Elisa Riccio, Alessandra Ruta, Luana Bigiotti, Carlo Carotti, Andrea Moretti, Sonia Cerra, Bruno Gioiello, Antimo Ferlin, Simone Puxeddu, Efisio Macchiarulo, Antonio Int J Mol Sci Article PD-1/PD-L1 protein complex is attracting a great deal of interest as a drug target for the design of immune therapies able to block its assembly. Although some biologic drugs have entered clinical use, their poor response rate in patients are demanding further efforts to design small molecule inhibitors of PD-1/PD-L1 complex with higher efficacy and optimal physicochemical properties. Dysregulation of pH in the tumor microenvironment is indeed one of the key mechanisms promoting drug resistance and lack of response in cancer therapy. Integrating computational and biophysical approaches, herein we report a screening campaign that has led to identifying VIS310 as a novel ligand of PD-L1, with physicochemical properties enabling a pH-dependent binding potency. Additional optimization efforts by analogue-based screening have been instrumental to disclosing VIS1201, which exhibits improved binding potency against PD-L1 and is able to inhibit PD-1/PD-L1 complex formation in a ligand binding displacement assay. While providing preliminary structure–activity relationships (SARs) of a novel class of PD-L1 ligands, our results lay the foundation for the discovery of immunoregulatory small molecules resilient to tumor microenvironmental conditions for escaping drug-resistance mechanisms. MDPI 2023-03-14 /pmc/articles/PMC10054428/ /pubmed/36982608 http://dx.doi.org/10.3390/ijms24065535 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Bianconi, Elisa Riccio, Alessandra Ruta, Luana Bigiotti, Carlo Carotti, Andrea Moretti, Sonia Cerra, Bruno Gioiello, Antimo Ferlin, Simone Puxeddu, Efisio Macchiarulo, Antonio Turning a Tumor Microenvironment Pitfall into Opportunity: Discovery of Benzamidoxime as PD-L1 Ligand with pH-Dependent Potency |
title | Turning a Tumor Microenvironment Pitfall into Opportunity: Discovery of Benzamidoxime as PD-L1 Ligand with pH-Dependent Potency |
title_full | Turning a Tumor Microenvironment Pitfall into Opportunity: Discovery of Benzamidoxime as PD-L1 Ligand with pH-Dependent Potency |
title_fullStr | Turning a Tumor Microenvironment Pitfall into Opportunity: Discovery of Benzamidoxime as PD-L1 Ligand with pH-Dependent Potency |
title_full_unstemmed | Turning a Tumor Microenvironment Pitfall into Opportunity: Discovery of Benzamidoxime as PD-L1 Ligand with pH-Dependent Potency |
title_short | Turning a Tumor Microenvironment Pitfall into Opportunity: Discovery of Benzamidoxime as PD-L1 Ligand with pH-Dependent Potency |
title_sort | turning a tumor microenvironment pitfall into opportunity: discovery of benzamidoxime as pd-l1 ligand with ph-dependent potency |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10054428/ https://www.ncbi.nlm.nih.gov/pubmed/36982608 http://dx.doi.org/10.3390/ijms24065535 |
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