期刊
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
卷 20, 期 5, 页码 1712-1717出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2010.01.079
关键词
Vitamin D; Antagonist; Co-factor; Nuclear receptor; Non-peptide; Molecular design; Protein interaction inhibitor
资金
- Ministry of Education, Culture, Sports, Science and Technology, Japan
- Japan Society for the Promotion of Science
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 alpha-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 mu M. 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 alpha-mediated transcription, indicating that it is not a non-selective inhibitor of other nuclear receptors. (C) 2010 Elsevier Ltd. All rights reserved.
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