Imidazo[2,1- b ]benzothiazol Derivatives as Potential Allosteric Inhibitors of the Glucocorticoid Receptor

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 anti-inflammatory 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.
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https://hal.umontpellier.fr/hal-02285732
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Soumis le : vendredi 13 septembre 2019 - 09:15:09
Dernière modification le : samedi 14 septembre 2019 - 01:27:01

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Michael Christodoulou, Federico Dapiaggi, Francesca Ghiringhelli, Stefano Pieraccini, Maurizio Sironi, et al.. Imidazo[2,1- b ]benzothiazol Derivatives as Potential Allosteric Inhibitors of the Glucocorticoid Receptor. ACS Medicinal Chemistry Letters, American Chemical Society, 2018, 9 (4), pp.339-344. ⟨10.1021/acsmedchemlett.7b00527⟩. ⟨hal-02285732⟩

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