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.

Imidazo[2,1-b]benzothiazol derivatives as potential allosteric inhibitors of the glucocorticoid receptor / M. Christodoulou, F. Dapiaggi, F. Ghiringhelli, S. Pieraccini, M. Sironi, M. Lucafo, D. Curci, G. Decorti, G. Stocco, C. Sekharchirumamilla, W.V. Berghe, P. Balaguer, B.Y. Michel, A. Burger, E.M. Beccalli, D. Passarella, N. Martinet. - In: ACS MEDICINAL CHEMISTRY LETTERS. - ISSN 1948-5875. - 9:4(2018 Apr), pp. 339-344. [10.1021/acsmedchemlett.7b00527]

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

M. Christodoulou
Primo
;
F. Dapiaggi;S. Pieraccini;M. Sironi;E.M. Beccalli;D. Passarella;
2018

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.
anti-inflammatory GCR like activity; GCR allosteric inhibition; Imidazo[2,1-b]benzoimidazole; Imidazo[2,1-b]benzothiazole; reduced GILZ expression; biochemistry; drug discovery3003 pharmaceutical science; organic chemistry
Settore CHIM/06 - Chimica Organica
Settore CHIM/08 - Chimica Farmaceutica
apr-2018
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/572972
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