Mechanism of Inhibition of the MeTC7 Ligand That Covalently Binds to VDR To Reduce PD-L1 Expression

Cancer-associated overexpression of the Vitamin D Receptor (VDR) is associated with good or poor prognosis, depending on the cancer type and stage. Here, we show that VDR is overexpressed in ovarian malignant tissues and upregulates PD-L1 surface expression in tumor cells, enabling immune evasion by the tumors. MeTC7, a VDR antagonist, has demonstrated strong inhibition of PD-L1 expression in vitro and in vivo. Using structural mass spectrometry and biophysical methods, we showed that MeTC7 binds covalently to VDR in the canonical ligand-binding pocket. Using ligand excess, additional covalently bound molecules were observed. Hydrogen-deuterium exchange mass spectrometry revealed that MeTC7 binding prevents optimal folding of the C-terminal region of VDR and impacts H10, which is part of the dimerization interface. Overall, our findings highlight a new mechanism of action for a VDR antagonist ligand and provide support for the use of the MeTC7 antagonist to inhibit PD-L1 and block tumorigenesis.

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Publication Details

Journal
Journal of Medicinal Chemistry
Published
2025-10-22
DOI
https://doi.org/10.1021/acs.jmedchem.5c02589
Primary Topic
Cancer Immunotherapy and Biomarkers
Type
article
Field-Weighted Citation Impact
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article

Mechanism of Inhibition of the MeTC7 Ligand That Covalently Binds to VDR To Reduce PD-L1 Expression

Naohiro Yano, Carole Peluso‐Iltis, Yuki Teramoto, J.-G. Castel et al.
Journal of Medicinal Chemistry
Cancer Immunotherapy and Biomarkers
article

Mechanism of Inhibition of the MeTC7 Ligand That Covalently Binds to VDR To Reduce PD-L1 Expression

Naohiro Yano, Carole Peluso‐Iltis, Yuki Teramoto, J.-G. Castel, Kyukwang Kim, Rachael B. Rowswell-Turner, Natacha Rochel, Richard G. Moore, Rakesh K. Singh, Aurora Silvestri, Sarah Cianférani, Judit Ősz, Angélique Sanchez Dafun, Hiroshi Miyamoto, Thierry Guiberteau, Negar Khazan
article en

Abstract

Cancer-associated overexpression of the Vitamin D Receptor (VDR) is associated with good or poor prognosis, depending on the cancer type and stage. Here, we show that VDR is overexpressed in ovarian malignant tissues and upregulates PD-L1 surface expression in tumor cells, enabling immune evasion by the tumors. MeTC7, a VDR antagonist, has demonstrated strong inhibition of PD-L1 expression in vitro and in vivo. Using structural mass spectrometry and biophysical methods, we showed that MeTC7 binds covalently to VDR in the canonical ligand-binding pocket. Using ligand excess, additional covalently bound molecules were observed. Hydrogen-deuterium exchange mass spectrometry revealed that MeTC7 binding prevents optimal folding of the C-terminal region of VDR and impacts H10, which is part of the dimerization interface. Overall, our findings highlight a new mechanism of action for a VDR antagonist ligand and provide support for the use of the MeTC7 antagonist to inhibit PD-L1 and block tumorigenesis.

Journal of Medicinal ChemistryVol. 68(21)
Gynecologic Oncology Group (US), Centre National de la Recherche Scientifique (FR), Brown University (US), Rhode Island Hospital (US), University of Rochester Medical Center (US), Institut de génétique et de biologie moléculaire et cellulaire (FR), Laboratoire de Spectrométrie Ionique et Moléculaire (FR), Protéomique, Réponse Inflammatoire et Spectrométrie de Masse (FR), French Clinical Research Infrastructure Network (FR), Université de Strasbourg (FR)
Openalex Percentile: Top 60%
Cancer Immunotherapy and Biomarkers
DOISourceOpenAlex
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