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

Fatemeh Sarmadi1, Amelia Caza2, Zhizhong Gao2

  • 1Department of Physiology, McGill University, 3655 Promenade Sir William Osler, Montreal, QC H3G 1Y6, Canada.

Journal of Medicinal Chemistry
|September 18, 2025
PubMed

Insights

A novel bifunctional molecule, AC-340, combines vitamin D receptor (VDR) agonism with histone deacetylase inhibition (HDACi). This VDR hyperagonist shows promise for enhanced cancer therapy by boosting VDR target gene expression.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • 1,25-Dihydroxyvitamin D (1,25D) analogs and histone deacetylase inhibitors (HDACi) show anticancer and immunomodulatory effects.
  • Tumor resistance to 1,25D monotherapy necessitates combination strategies, such as with HDACi, to restore efficacy.

Purpose of the Study:

  • To introduce AC-340, a novel bifunctional molecule integrating HDACi into a VDR agonist.
  • To evaluate the in vitro efficacy and molecular mechanisms of AC-340 in melanoma models.

Main Methods:

  • In vitro testing in multiple melanoma models.
  • RNA sequencing (RNaseq) analysis of B16-F10 mouse melanoma cells.
  • Comparative structural studies and ChIP-qPCR to assess VDR interactions and coactivator recruitment.
  • Analysis of H3K27 acetylation levels on VDR target genes.

Main Results:

  • AC-340 demonstrated robust bifunctionality in vitro.
  • RNaseq revealed AC-340 superinduces a wide range of VDR target genes.
  • AC-340 exhibits enhanced VDR coactivator binding and recruitment of CBP compared to 1,25D.
  • AC-340 increases H3K27 acetylation of VDR target genes, indicating heightened transcriptional activity.

Conclusions:

  • AC-340 acts as a VDR hyperagonist due to enhanced VDR interactions and HDACi activity.
  • AC-340 holds potential for effective mono- or combination therapies in various cancer models.

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