9rcg | pdb_00009rcg
Vitamin D receptor complex with a vitamin D receptor agonist/histone deacetylase inhibitor hybrid molecule
Structural highlights
FunctionVDRA_DANRE Nuclear hormone receptor. Transcription factor that mediates the action of vitamin D3 by controlling the expression of hormone sensitive genes. Regulates transcription of hormone sensitive genes via its association with the WINAC complex, a chromatin-remodeling complex. Plays a central role in calcium homeostasis.[1] Publication Abstract from PubMed1,25-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. Hyperagonism of a Vitamin D Receptor Agonist/Histone Deacetylase Inhibitor Hybrid Molecule.,Sarmadi F, Caza A, Gao Z, Rochel N, Gleason JL, White JH J Med Chem. 2025 Sep 18. doi: 10.1021/acs.jmedchem.5c01932. PMID:40968099[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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