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...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-03-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/6/5535 |
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| author | Elisa Bianconi Alessandra Riccio Luana Ruta Carlo Bigiotti Andrea Carotti Sonia Moretti Bruno Cerra Antimo Gioiello Simone Ferlin Efisio Puxeddu Antonio Macchiarulo |
| author_facet | Elisa Bianconi Alessandra Riccio Luana Ruta Carlo Bigiotti Andrea Carotti Sonia Moretti Bruno Cerra Antimo Gioiello Simone Ferlin Efisio Puxeddu Antonio Macchiarulo |
| author_sort | Elisa Bianconi |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-03-11T06:25:53Z |
| format | Article |
| id | doaj.art-390a90695a4140999d9d93d54335d7ae |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-11T06:25:53Z |
| publishDate | 2023-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-390a90695a4140999d9d93d54335d7ae2023-11-17T11:35:17ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-03-01246553510.3390/ijms24065535Turning a Tumor Microenvironment Pitfall into Opportunity: Discovery of Benzamidoxime as PD-L1 Ligand with pH-Dependent PotencyElisa Bianconi0Alessandra Riccio1Luana Ruta2Carlo Bigiotti3Andrea Carotti4Sonia Moretti5Bruno Cerra6Antimo Gioiello7Simone Ferlin8Efisio Puxeddu9Antonio Macchiarulo10Department of Pharmaceutical Sciences, University of Perugia, Via del liceo n.1, 06123 Perugia, ItalyDepartment of Pharmaceutical Sciences, University of Perugia, Via del liceo n.1, 06123 Perugia, ItalyDepartment of Pharmaceutical Sciences, University of Perugia, Via del liceo n.1, 06123 Perugia, ItalyDepartment of Pharmaceutical Sciences, University of Perugia, Via del liceo n.1, 06123 Perugia, ItalyDepartment of Pharmaceutical Sciences, University of Perugia, Via del liceo n.1, 06123 Perugia, ItalyDepartment of Medicine and Surgery, University of Perugia, P.le L. Severi, 06132 Perugia, ItalyDepartment of Pharmaceutical Sciences, University of Perugia, Via del liceo n.1, 06123 Perugia, ItalyDepartment of Pharmaceutical Sciences, University of Perugia, Via del liceo n.1, 06123 Perugia, ItalySterling S.p.A., Via della Carboneria n.30, 06073 Corciano, ItalyDepartment of Medicine and Surgery, University of Perugia, P.le L. Severi, 06132 Perugia, ItalyDepartment of Pharmaceutical Sciences, University of Perugia, Via del liceo n.1, 06123 Perugia, ItalyPD-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.https://www.mdpi.com/1422-0067/24/6/5535fragment-based drug designmolecular dockingbiophysicsvirtual screeningthermophoresis |
| spellingShingle | Elisa Bianconi Alessandra Riccio Luana Ruta Carlo Bigiotti Andrea Carotti Sonia Moretti Bruno Cerra Antimo Gioiello Simone Ferlin Efisio Puxeddu Antonio Macchiarulo Turning a Tumor Microenvironment Pitfall into Opportunity: Discovery of Benzamidoxime as PD-L1 Ligand with pH-Dependent Potency International Journal of Molecular Sciences fragment-based drug design molecular docking biophysics virtual screening thermophoresis |
| 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 | fragment-based drug design molecular docking biophysics virtual screening thermophoresis |
| url | https://www.mdpi.com/1422-0067/24/6/5535 |
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