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

doi:10.1021/acsmedchemlett.7b00527

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 journal › Article

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 language	English
Pages (from-to)	339-344
Number of pages	6
Journal	ACS Medicinal Chemistry Letters
Volume	9
Issue number	4
DOIs	https://doi.org/10.1021/acsmedchemlett.7b00527
Publication status	Published - Jan 1 2018

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

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Christodoulou, M. S., Dapiaggi, F., Ghiringhelli, F., Pieraccini, S., Sironi, M., Lucafo, M., Curci, D., Decorti, G., Stocco, G., SekharChirumamilla, C., Berghe, W. V., Balaguer, P., Michel, B. Y., Burger, A., Beccalli, E. M., Passarella, D., & Martinet, N. (2018). Imidazo[2,1-b]benzothiazol derivatives as potential allosteric inhibitors of the glucocorticoid receptor. ACS Medicinal Chemistry Letters, 9(4), 339-344. https://doi.org/10.1021/acsmedchemlett.7b00527

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 journal › Article

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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