Bifunctionality and Antitumor Efficacy of ZG-126, a Vitamin D Receptor Agonist/Histone Deacetylase Inhibitor Hybrid Molecule

Analogues of hormonal
vitamin D, 1,25-dihydroxyvitamin D (1,25D),
signal through the nuclear vitamin D receptor (VDR). They have potential
in combination therapies with other anticancer agents such as histone
deacetylase inhibitors (HDACi’s). Here, we characterize the
ZG series of hybrid compounds that combine HDACi within the backbone
of a VDR agonist. All display improved solubility, with ZG-126 being
the most robustly bifunctional molecule in multiple cell lines. ZG-126
is well tolerated and strongly induces VDR target gene expression
in vivo at therapeutic doses. Its antitumor efficacy is superior to
1,25D and the HDACi SAHA, separately or together, in mouse models
of melanoma and triple-negative breast cancer (TNBC). Notably, ZG-126
treatment reduces metastases almost 4-fold in an aggressive TNBC model.
ZG-126 also reduces total macrophage infiltration and the proportion
of immunosuppressive M2-polarized macrophages in TNBC tumors by 2-fold.
ZG-126 thus represents a bifunctional and efficacious anticancer agent
with improved physicochemical properties.