9RCG

Vitamin D receptor complex with a vitamin D receptor agonist/histone deacetylase inhibitor hybrid molecule

This is a non-PDB format compatible entry.

Summary for 9RCG

• Entry DOI: 10.2210/pdb9rcg/pdb
• Descriptor: Vitamin D3 receptor A, Nuclear receptor coactivator 2, 4-[4-[3-[5-[(3~{S})-4,4-dimethyl-3-oxidanyl-pentyl]-4-methyl-1,3-thiazol-2-yl]pentan-3-yl]phenoxy]-~{N}-oxidanyl-butanamide, ... (4 entities in total)
• Functional Keywords: vdr complex, vdr ligand, superagonist, histone deacetylase inhibitor, transcription
• Biological source: Danio rerio (zebrafish); More
• Total number of polymer chains: 2
• Total formula weight: 36117.21

Authors

Rochel, N. (deposition date: 2025-05-28, release date: 2025-10-01, Last modification date: 2025-10-22)

Primary citation

Sarmadi, F.,Caza, A.,Gao, Z.,Rochel, N.,Gleason, J.L.,White, J.H.
Hyperagonism of a Vitamin D Receptor Agonist/Histone Deacetylase Inhibitor Hybrid Molecule.
J.Med.Chem., 68:20675-20688, 2025

PubMed Abstract: 1,25-Dihydroxyvitamin D (1,25D) analogs engage the vitamin D receptor (VDR) and can exert anticancer and immunomodulatory effects. Although tumors often resist 1,25D monotherapy, combining VDR agonism with histone deacetylase inhibitors (HDACi) restores anticancer efficacy. Here, we present AC-340, a novel bifunctional molecule that incorporates HDACi into a VDR agonist backbone. Besides its robust bifunctionality in vitro in multiple melanoma models, RNaseq analysis of B16-F10 mouse melanoma cells revealed that AC-340 superinduces the expression of a broad array of VDR target genes. Comparative structural studies and ChIP-qPCR revealed that AC-340 forms more interactions than 1,25D with residues in the VDR coactivator binding domain, leading to more efficacious recruitment of coactivator CBP. This, likely coupled with AC-340 HDACi activity, leads to elevated H3K27 acetylation of VDR target genes, a mark of active transcription. Thus, AC-340 functions as a VDR hyperagonist and should be efficacious in mono- or combination therapies against multiple cancer models.

PubMed: 40968099
DOI: 10.1021/acs.jmedchem.5c01932

Experimental method

X-RAY DIFFRACTION (2.1 Å)