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

ABSTRACT: 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 agg

SUBMITTER: Sarmadi F 

PROVIDER: S-EPMC11249012 | biostudies-literature | 2024 Jul

REPOSITORIES: biostudies-literature