Carboxamide Derivatives Are Potential Therapeutic AHR Ligands for Restoring IL-4 Mediated Repression of Epidermal Differentiation Proteins

Atopic dermatitis (AD) is a common T-helper 2 (Th2) lymphocyte-mediated chronic inflammatory skin disease characterized by disturbed epidermal differentiation (e.g., ( ) expression) and diminished skin barrier function. Therapeutics targeting the aryl hydrocarbon receptor (AHR), such as coal tar and...

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Bibliographic Details
Published in:International journal of molecular sciences 2022-02, Vol.23 (3), p.1773
Main Authors: Rikken, Gijs, van den Brink, Noa J M, van Vlijmen-Willems, Ivonne M J J, van Erp, Piet E J, Pettersson, Lars, Smits, Jos P H, van den Bogaard, Ellen H
Format: Article
Language:English
Subjects:
Agonists
aryl hydrocarbon receptor
Atopic dermatitis
Basic Helix-Loop-Helix Transcription Factors - metabolism
Bioavailability
carboxamide-3-quinoline
Cell Differentiation
Cells, Cultured
Coal tar
Cytokines
Differentiation
Disease
drug development
Drug dosages
Eczema
Filaggrin
Filaggrin Proteins - genetics
Gene expression
Gene Expression Regulation
Hep G2 Cells
Humans
Interleukin 4
Keratinocytes - drug effects
Keratinocytes - metabolism
Keratinocytes - physiology
Ligands
Lymphocytes
Lymphocytes T
Metabolism
Metabolites
Protein expression
Proteins
Quinolones - pharmacology
Receptors, Aryl Hydrocarbon - metabolism
Signal Transduction
Skin diseases
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Summary:Atopic dermatitis (AD) is a common T-helper 2 (Th2) lymphocyte-mediated chronic inflammatory skin disease characterized by disturbed epidermal differentiation (e.g., ( ) expression) and diminished skin barrier function. Therapeutics targeting the aryl hydrocarbon receptor (AHR), such as coal tar and tapinarof, are effective in AD, yet new receptor ligands with improved potency or bioavailability are in demand to expand the AHR-targeting therapeutic arsenal. We found that carboxamide derivatives from laquinimod, tasquinimod, and roquinimex can activate AHR signaling at low nanomolar concentrations. Tasquinimod derivative (IMA-06504) and its prodrug (IMA-07101) provided full agonist activity and were most effective to induce and other epidermal differentiation proteins, and counteracted IL-4 mediated repression of terminal differentiation. Partial agonist activity by other derivatives was less efficacious. The previously reported beneficial safety profile of these novel small molecules, and the herein reported therapeutic potential of specific carboxamide derivatives, provides a solid rationale for further preclinical assertation.
ISSN:1422-0067
1661-6596
1422-0067
DOI:10.3390/ijms23031773