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 | |
| Publication status | Published - Jan 1 2018 |
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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 journal › Article
}
TY - JOUR
T1 - Imidazo[2,1-b]benzothiazol derivatives as potential allosteric inhibitors of the glucocorticoid receptor
AU - Christodoulou, Michael S.
AU - Dapiaggi, Federico
AU - Ghiringhelli, Francesca
AU - Pieraccini, Stefano
AU - Sironi, Maurizio
AU - Lucafo, Marianna
AU - Curci, Debora
AU - Decorti, Giuliana
AU - Stocco, Gabriele
AU - SekharChirumamilla, Chandra
AU - Berghe, Wim Vanden
AU - Balaguer, Patrick
AU - Michel, Benoît Y.
AU - Burger, Alain
AU - Beccalli, Egle M.
AU - Passarella, Daniele
AU - Martinet, Nadine
PY - 2018/1/1
Y1 - 2018/1/1
N2 - 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.
AB - 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.
KW - Anti-inflammatory GCR like activity
KW - GCR allosteric inhibition
KW - Imidazo[2,1-b]benzoimidazole
KW - Imidazo[2,1-b]benzothiazole
KW - Reduced GILZ expression
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UR - http://www.scopus.com/inward/citedby.url?scp=85045182931&partnerID=8YFLogxK
U2 - 10.1021/acsmedchemlett.7b00527
DO - 10.1021/acsmedchemlett.7b00527
M3 - Article
VL - 9
SP - 339
EP - 344
JO - ACS Medicinal Chemistry Letters
JF - ACS Medicinal Chemistry Letters
SN - 1948-5875
IS - 4
ER -