Imidazo[2,1-b]benzothiazol derivatives as potential allosteric inhibitors of the glucocorticoid receptor

Michael S. Christodoulou, Federico Dapiaggi, Francesca Ghiringhelli, Stefano Pieraccini, Maurizio Sironi, Marianna Lucafo, Debora Curci, Giuliana Decorti, Gabriele Stocco, Chandra SekharChirumamilla, Wim Vanden Berghe, Patrick Balaguer, Benoît Y. Michel, Alain Burger, Egle M. Beccalli, Daniele Passarella, Nadine Martinet

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Glucocorticoid receptor (GCR) transactivation reporter gene assays were used as an initial high-throughput screening on a diversified library of 1200 compounds for their evaluation as GCR antagonists. A class of imidazo[2,1-b]benzothiazole and imidazo[2,1-b]benzoimidazole derivatives were identified for their ability to modulate GCR transactivation and antiinflammatory transrepression effects utilizing GCR and NF-κB specific reporter gene assays. Modeling studies on the crystallographic structure of the GCR ligand binding domain provided three new analogues bearing the tetrahydroimidazo[2,1-b]benzothiazole scaffold able to antagonize the GCR in the presence of dexamethasone (DEX) and also defined their putative binding into the GCR structure. Both mRNA level measures of GCR itself and its target gene GILZ, on cells treated with the new analogues, showed a GCR transactivation inhibition, thus suggesting a potential allosteric inhibition of the GCR.

Original languageEnglish
Pages (from-to)339-344
Number of pages6
JournalACS Medicinal Chemistry Letters
Volume9
Issue number4
DOIs
Publication statusPublished - Jan 1 2018

Fingerprint

Glucocorticoid Receptors
Derivatives
Transcriptional Activation
Genes
Reporter Genes
Assays
Bearings (structural)
Scaffolds
Dexamethasone
Screening
Anti-Inflammatory Agents
Throughput
Ligands
Messenger RNA

Keywords

  • Anti-inflammatory GCR like activity
  • GCR allosteric inhibition
  • Imidazo[2,1-b]benzoimidazole
  • Imidazo[2,1-b]benzothiazole
  • Reduced GILZ expression

ASJC Scopus subject areas

  • Biochemistry
  • Drug Discovery
  • Organic Chemistry

Cite this

Imidazo[2,1-b]benzothiazol derivatives as potential allosteric inhibitors of the glucocorticoid receptor. / Christodoulou, Michael S.; Dapiaggi, Federico; Ghiringhelli, Francesca; Pieraccini, Stefano; Sironi, Maurizio; Lucafo, Marianna; Curci, Debora; Decorti, Giuliana; Stocco, Gabriele; SekharChirumamilla, Chandra; Berghe, Wim Vanden; Balaguer, Patrick; Michel, Benoît Y.; Burger, Alain; Beccalli, Egle M.; Passarella, Daniele; Martinet, Nadine.

In: ACS Medicinal Chemistry Letters, Vol. 9, No. 4, 01.01.2018, p. 339-344.

Research output: Contribution to journalArticle

Christodoulou, MS, Dapiaggi, F, Ghiringhelli, F, Pieraccini, S, Sironi, M, Lucafo, M, Curci, D, Decorti, G, Stocco, G, SekharChirumamilla, C, Berghe, WV, Balaguer, P, Michel, BY, Burger, A, Beccalli, EM, Passarella, D & Martinet, N 2018, 'Imidazo[2,1-b]benzothiazol derivatives as potential allosteric inhibitors of the glucocorticoid receptor', ACS Medicinal Chemistry Letters, vol. 9, no. 4, pp. 339-344. https://doi.org/10.1021/acsmedchemlett.7b00527
Christodoulou, Michael S. ; Dapiaggi, Federico ; Ghiringhelli, Francesca ; Pieraccini, Stefano ; Sironi, Maurizio ; Lucafo, Marianna ; Curci, Debora ; Decorti, Giuliana ; Stocco, Gabriele ; SekharChirumamilla, Chandra ; Berghe, Wim Vanden ; Balaguer, Patrick ; Michel, Benoît Y. ; Burger, Alain ; Beccalli, Egle M. ; Passarella, Daniele ; Martinet, Nadine. / Imidazo[2,1-b]benzothiazol derivatives as potential allosteric inhibitors of the glucocorticoid receptor. In: ACS Medicinal Chemistry Letters. 2018 ; Vol. 9, No. 4. pp. 339-344.
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