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.