Structural highlights
Function
VDRA_DANRE Nuclear hormone receptor. Transcription factor that mediates the action of vitamin D3 by controlling the expression of hormone sensitive genes. Regulates transcription of hormone sensitive genes via its association with the WINAC complex, a chromatin-remodeling complex. Plays a central role in calcium homeostasis.[1]
Publication Abstract from PubMed
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 approximately 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.
Synthetically accessible non-secosteroidal hybrid molecules combining vitamin d receptor agonism and histone deacetylase inhibition.,Fischer J, Wang TT, Kaldre D, Rochel N, Moras D, White JH, Gleason JL Chem Biol. 2012 Aug 24;19(8):963-71. PMID:22921063[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Ciesielski F, Rochel N, Moras D. Adaptability of the Vitamin D nuclear receptor to the synthetic ligand Gemini: remodelling the LBP with one side chain rotation. J Steroid Biochem Mol Biol. 2007 Mar;103(3-5):235-42. Epub 2007 Jan 10. PMID:17218092 doi:http://dx.doi.org/10.1016/j.jsbmb.2006.12.003
- ↑ Fischer J, Wang TT, Kaldre D, Rochel N, Moras D, White JH, Gleason JL. Synthetically accessible non-secosteroidal hybrid molecules combining vitamin d receptor agonism and histone deacetylase inhibition. Chem Biol. 2012 Aug 24;19(8):963-71. PMID:22921063 doi:http://dx.doi.org/10.1016/j.chembiol.2012.05.024
