Hyperagonism of a Vitamin D Receptor Agonist/Histone Deacetylase Inhibitor Hybrid Molecule

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.