In vitro pharmacological profiling of ITE amide bioisosteric aryl hydrocarbon receptor agonist
- 1Department of Cell Biology and Genetics, Faculty of Science, Palacký University , ,
- 2Department of Organic Chemistry, Faculty of Science, Palacký University , ,
Abstract
Previously, we reported ITE-derived bioisostere 2-(1 H -indole-3-carbonyl)-N-methyl thiazole-4-carboxamide (ITE-CONHCH ₃ ) as a high-affinity ligand and potent agonist of the aryl hydrocarbon receptor (AhR) with anti-colitis properties. In the current study, we present its initial in vitro pharmacological profiling. Physicochemical analysis revealed low aqueous solubility (22 µM), excellent chemical stability in human and mouse plasma, and strong plasma protein binding (>98%). Off-target screening against steroid and nuclear receptors confirmed high AhR selectivity. In Caco-2 cells, ITE-CONHCH ₃ exhibited high permeability with no active efflux. Interestingly, the compound partitioned substantially into mouse red blood cells (47%) but only weakly into human RBCs (16%). In reporter gene assays, ITE-CONHCH ₃ displayed ∼40-fold higher agonist potency in human cells compared to mouse cells. Its ability to activate AhR was further validated by a cell-free AhR-ARNT heterodimerization assay and by the induction of canonical ( CYP1A1 ) and non-canonical ( PAI-1 ) genes expression in Caco-2 cells. In conclusion, ITE-CONHCH ₃ possesses a favorable pharmacological profile supporting its potential preclinical development. However, the observed differences in RBC partitioning and AhR potency between species must be considered when interpreting mouse-derived data.
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BibTeX
@article{dvorak2026vitro,
title = {{In vitro pharmacological profiling of ITE amide bioisosteric aryl hydrocarbon receptor agonist}},
author = {Zdeněk Dvořák and Aneta Grycová and Radim Vrzal and Miroslav Soural and Iveta Zůvalová and Jakub Přikryl},
journal = {Frontiers in pharmacology},
year = {2026},
month = oct,
doi = {10.3389/fphar.2026.1931941},
url = {https://europepmc.org/article/PMC/PMC13672210},
note = {CC BY},
}
RIS
TY - JOUR
TI - In vitro pharmacological profiling of ITE amide bioisosteric aryl hydrocarbon receptor agonist
AU - Zdeněk Dvořák
AU - Aneta Grycová
AU - Radim Vrzal
AU - Miroslav Soural
AU - Iveta Zůvalová
AU - Jakub Přikryl
PY - 2026
DA - 2026/10/02
JO - Frontiers in pharmacology
DO - 10.3389/fphar.2026.1931941
UR - https://europepmc.org/article/PMC/PMC13672210
AB - Previously, we reported ITE-derived bioisostere 2-(1 H -indole-3-carbonyl)-N-methyl thiazole-4-carboxamide (ITE-CONHCH ₃ ) as a high-affinity ligand and potent agonist of the aryl hydrocarbon receptor (AhR) with anti-colitis properties. In the current study, we present its initial in vitro pharmacological profiling. Physicochemical analysis revealed low aqueous solubility (22 µM), excellent chemical stability in human and mouse plasma, and strong plasma protein binding (>98%). Off-target screening against steroid and nuclear receptors confirmed high AhR selectivity. In Caco-2 cells, ITE-CONHCH ₃ exhibited high permeability with no active efflux. Interestingly, the compound partitioned substantially into mouse red blood cells (47%) but only weakly into human RBCs (16%). In reporter gene assays, ITE-CONHCH ₃ displayed ∼40-fold higher agonist potency in human cells compared to mouse cells. Its ability to activate AhR was further validated by a cell-free AhR-ARNT heterodimerization assay and by the induction of canonical ( CYP1A1 ) and non-canonical ( PAI-1 ) genes expression in Caco-2 cells. In conclusion, ITE-CONHCH ₃ possesses a favorable pharmacological profile supporting its potential preclinical development. However, the observed differences in RBC partitioning and AhR potency between species must be considered when interpreting mouse-derived data.
SN - 1663-9812
ER -