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

Yusuke Mita, Kosuke Dodo, Tomomi Noguchi-Yachide, Hiroyuki Miyachi, Makoto Makishima, Yuichi Hashimoto, Minoru Ishikawa

Research output: Contribution to journalArticle

29 Citations (Scopus)

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 languageEnglish
Pages (from-to)1712-1717
Number of pages6
JournalBioorganic and Medicinal Chemistry Letters
Volume20
Issue number5
DOIs
Publication statusPublished - Mar 1 2010
Externally publishedYes

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

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  • Cite this

    Mita, Y., Dodo, K., Noguchi-Yachide, T., Miyachi, H., Makishima, M., Hashimoto, Y., & Ishikawa, M. (2010). LXXLL peptide mimetics as inhibitors of the interaction of vitamin D receptor with coactivators. Bioorganic and Medicinal Chemistry Letters, 20(5), 1712-1717. https://doi.org/10.1016/j.bmcl.2010.01.079