Turning a Tumor Microenvironment Pitfall into Opportunity: Discovery of Benzamidoxime as PD-L1 Ligand with
Elisa Bianconi1, Alessandra Riccio1, Luana Ruta1
1Department of Pharmaceutical Sciences, University of Perugia, Via del liceo n.1, 06123 Perugia, Italy.
Abstract:
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.
Insights
Researchers identified novel small molecules, VIS310 and VIS1201, that target the PD-1/PD-L1 complex. These inhibitors show pH-dependent potency, offering potential to overcome drug resistance in cancer immunotherapy.
Area of Science:
- Immunology
- Pharmacology
- Computational Chemistry
Background:
- The programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) pathway is a key target for cancer immunotherapy.
- Existing biologic drugs targeting PD-1/PD-L1 have limited efficacy and face challenges due to tumor microenvironment conditions like pH dysregulation, leading to drug resistance.
Purpose of the Study:
- To discover novel small molecule inhibitors of the PD-1/PD-L1 complex with improved efficacy and optimal physicochemical properties.
- To develop immunoregulatory agents that are resilient to the tumor microenvironment and can overcome drug resistance mechanisms.
Main Methods:
- Integrated computational and biophysical screening approaches were employed to identify ligands for PD-L1.
- Analogue-based screening was utilized for further optimization of identified compounds.
- Ligand binding displacement assays were performed to assess the inhibition of PD-1/PD-L1 complex formation.
Main Results:
- VIS310 was identified as a novel PD-L1 ligand with pH-dependent binding potency.
- VIS1201, an optimized analogue, demonstrated improved binding potency against PD-L1.
- VIS1201 successfully inhibited PD-1/PD-L1 complex formation in vitro.
Conclusions:
- A novel class of PD-L1 ligands has been discovered, with preliminary structure-activity relationships established.
- The identified small molecules, particularly VIS1201, show potential for developing next-generation cancer immunotherapies that overcome drug resistance.
- These findings provide a foundation for designing immunoregulatory small molecules effective in challenging tumor microenvironmental conditions.
