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; Lucafò, Marianna; Curci, Debora; Decorti, Giuliana; Stocco, Gabriele; Sekhar Chirumamilla, Chandra; Vanden Berghe, Wim; Balaguer, Patrick; Michel, Benoît Y.; Burger, Alain; Beccalli, Egle M.; Passarella, Daniele; Martinet, Nadine

doi:10.1021/acsmedchemlett.7b00527.s001

ml7b00527_si_001.pdf (1.35 MB)

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

journal contribution

posted on 26.02.2018, 00:00 authored by Michael S. Christodoulou, Federico Dapiaggi, Francesca Ghiringhelli, Stefano Pieraccini, Maurizio Sironi, Marianna Lucafò, Debora Curci, Giuliana Decorti, Gabriele Stocco, Chandra Sekhar Chirumamilla, Wim Vanden Berghe, Patrick Balaguer, Benoît Y. Michel, Alain Burger, Egle M. Beccalli, Daniele Passarella, Nadine Martinet

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.