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LXXLL peptide mimetics as inhibitors of the interaction of vitamin D receptor with coactivators

Authors
Journal
Bioorganic & Medicinal Chemistry Letters
0960-894X
Publisher
Elsevier
Publication Date
Volume
20
Issue
5
Identifiers
DOI: 10.1016/j.bmcl.2010.01.079
Keywords
  • Vitamin D
  • Antagonist
  • Co-Factor
  • Nuclear Receptor
  • Non-Peptide
  • Molecular Design
  • Protein Interaction Inhibitor
Disciplines
  • Biology
  • Design
  • Medicine

Abstract

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 IC 50 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.

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