ml7b00527_si_001.pdf (1.35 MB)
Download fileImidazo[2,1‑b]benzothiazol Derivatives as Potential Allosteric Inhibitors of the Glucocorticoid Receptor
journal contribution
posted on 2018-02-26, 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 MartinetGlucocorticoid
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.
History
Usage metrics
Read the peer-reviewed publication
Categories
Keywords
DEXGCR structureGCR ligand binding domaintransactivation reporter gene assaysPotential Allosteric Inhibitorsbenzothiazol DerivativesNF -κBtarget gene GILZGCR transactivation inhibitionallosteric inhibitionmodeling studieshigh-throughput screeninganti-inflammatory transrepression effectsmRNA level measures1200 compoundsreporter gene assaysGCR transactivationGCR antagonistsGlucocorticoid Receptor Glucocorticoid receptor