4FHI

Development of synthetically accessible non-secosteroidal hybrid molecules combining vitamin D receptor agonism and histone deacetylase inhibition

Summary for 4FHI

• Entry DOI: 10.2210/pdb4fhi/pdb
• Related: 4FHH
• Descriptor: Vitamin Nuclear Receptor, SRC-1, N-hydroxy-2-{4-[3-(4-{[(2R)-2-hydroxy-3,3-dimethylbutyl]oxy}-3-methylphenyl)pentan-3-yl]-2-methylphenoxy}acetamide, ... (4 entities in total)
• Functional Keywords: ligand binding domain alpha helical sandwich, alpha helical sandwich, transcription factor, dna coregulators, phosphorylation, nucleus, transcription-protein binding-inhibitor complex, transcription/protein binding/inhibitor
• Biological source: Danio Rerio; More
• Total number of polymer chains: 2
• Total formula weight: 35954.01

Authors

Fischer, J.,Wang, T.T.,Kaldre, D.,Rochel, N.,Moras, D.,White, J.H.,Gleason, J.L. (deposition date: 2012-06-06, release date: 2012-09-19, Last modification date: 2024-02-28)

Primary citation

Fischer, J.,Wang, T.T.,Kaldre, D.,Rochel, N.,Moras, D.,White, J.H.,Gleason, J.L.
Synthetically accessible non-secosteroidal hybrid molecules combining vitamin d receptor agonism and histone deacetylase inhibition.
Chem.Biol., 19:963-971, 2012

PubMed Abstract: 1,25-Dihydroxyvitamin D(3) (1,25D), the hormonal form of vitamin D, and several analogs have failed as monotherapies for cancer because of poor efficacy or acquired resistance. However, 1,25D analogs are amenable to bifunctionalization. Preclinical studies have revealed combinatorial effects of 1,25D analogs and histone deacetylase inhibitors (HDACi). Secosteroidal hybrid molecules combining vitamin D receptor (VDR) agonism with HDACi displayed enhanced efficacy but are laborious to synthesize. Here, we have developed easily assembled, fully integrated, non-secosteroidal VDR agonist/HDACi hybrids. The most promising are full VDR agonists with ~10-fold lower potency than 1,25D. Structure/function studies revealed that antiproliferative activity against 1,25D-resistant squamous carcinoma cells required VDR agonism and HDACi. Remarkably, modeling and X-ray crystallography reveal non-secosteroidal hybrids bind in the VDR ligand binding domain in the opposite orientation of their secosteroidal counterparts.

PubMed: 22921063
DOI: 10.1016/j.chembiol.2012.05.024

Experimental method

X-RAY DIFFRACTION (2.4 Å)