1220099-45-5Relevant academic research and scientific papers
LXXLL peptide mimetics as inhibitors of the interaction of vitamin D receptor with coactivators
Mita, Yusuke,Dodo, Kosuke,Noguchi-Yachide, Tomomi,Miyachi, Hiroyuki,Makishima, Makoto,Hashimoto, Yuichi,Ishikawa, Minoru
scheme or table, p. 1712 - 1717 (2010/08/06)
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.
