Abstract
Suppression of vitamin D receptor (VDR)-mediated transcription is expected be of therapeutic value in Paget's disease. Once an agonist activates VDR, recruitment of additional coactivator proteins is essential for transcription. Neither non-secosteroidal VDR antagonists nor non-peptide coactivator binding inhibitors for VDR have been reported so far. Based on the X-ray structure of VDR and an LXXLL-containing peptide fragment of the coactivator (where L is leucine and X is any amino acid), which adopts a partially α-helical conformation, benzodiazepine molecules were rationally designed as non-peptide coactivator mimetics. TR-FRET assay showed that the synthesized compounds inhibited the interaction between VDR and a coactivator peptide fragment. Compound 2 showed an IC50 of 20 μM. Compound 2 also inhibited VDR-mediated transcription, and this activity was independent of the concentration of co-existing agonist. Furthermore, compound 2 did not inhibit estrogen receptor α-mediated transcription, indicating that it is not a non-selective inhibitor of other nuclear receptors.
Original language | English |
---|---|
Pages (from-to) | 1712-1717 |
Number of pages | 6 |
Journal | Bioorganic and Medicinal Chemistry Letters |
Volume | 20 |
Issue number | 5 |
DOIs | |
Publication status | Published - 2010 Mar 1 |
Externally published | Yes |
Keywords
- Antagonist
- Co-factor
- Molecular design
- Non-peptide
- Nuclear receptor
- Protein interaction inhibitor
- Vitamin D
ASJC Scopus subject areas
- Biochemistry
- Molecular Medicine
- Molecular Biology
- Pharmaceutical Science
- Drug Discovery
- Clinical Biochemistry
- Organic Chemistry