Structural Analysis of VDR Complex with ZK168281 Antagonist

Abstract

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Identification of a Vitamin-D Receptor Antagonist, MeTC7, which Inhibits the Growth of Xenograft and Transgenic Tumors In Vivo

“…Loss of TYR143, HIS305, and ARG274 interactions, which are critical for hydrogen-binding interactions of 1 , may account for the antagonistic attributes of 5 , similar to the effects of mutations at HIS305 along with ARG274 residues, which was shown to generate antagonistic effects (Figure e–g). Structurally, 5 differs from the literature , -described VDR antagonists TEI-9647 ( 2 ) and TEI-9648 ( 3 ). 5 carries a highly constrained heteroatom-rich-tetracyclic ring system derived from the conjugated diene system of 6 , the precursor of Vitamin-D, whereas 2 and 3 retain the classic Vitamin-D scaffold but have the C25 carbon converted into a five-membered lactone ring.…”

“…Notably, Sherman et al 50 showed that as an adjuvant Vitamin-D reprograms tumor stroma transcriptionally and enables chemotherapeutic responses in pancreatic ductal adenocarcinoma (PDA). Similarly, while the role of Vitamin-D/VDR in upregulation of PD-L1 on ovarian cancer (unpublished data) and leukemia and head and neck cancer cells 23 is concerning in the context of malignancies, there lies a very promising opportunity to use 1 to convert a cold-tumor type like PDA and ovarian cancer into a PD-L1-enriched hot-tumor type that can be better targeted by immune checkpoint antibodies and/or 5 .…”

“…Compared to agonists, the development of VDR antagonists has lagged behind. , Following our previously described approach of the Diels–Alder modification of secosteroidal scaffolds that generated earlier classes of VDR antagonists [MT19c ( 4 ) and PT19c], ,, 5 was synthesized. 5 showed superior VDR inhibition than 4 and PT19c without incurring any agonistic activity and exhibited noteworthy NR selectivity against PPAR-γ and RXRα, the two closely related members of the VDR-NR family (Figure c,d).…”

“…Progress in inhibiting VDR has remained hampered by the unavailability of pharmacologically pure VDR antagonists. , Currently known VDR antagonists can exhibit residual agonistic effects, , and their therapeutic effects have yet to be evaluated in animal models for malignancies. In addition, the synthesis of the literature-described VDR antagonists including TEI-9647 ( 2 ) and TEI-9648 ( 3 ) (Figure ) requires multiple synthesis steps and is challenging.…”

Vitamin D and Its Receptor from a Structural Perspective

“…NR is a highly dynamic scaffold protein and VDR LBD ( Figure 2 C) in a similar way to other NRs, is dynamic and only stabilized into a fixed conformation upon ligand binding. The dynamics of ligand binding process by VDR has been investigated by NMR [ 32 ] and HDX-MS [ 33 , 34 , 35 ]. These studies revealed that the entire C-terminal of VDR LBD in its apo state is very dynamic, with 80% of amide hydrogen exchange.…”