Phenylalanine amide derivatives promote FLG expression via AHR activation in normal human epidermal keratinocytes

Filaggrin (FLG) is one of the major components expressed in terminally differentiated keratinocytes and critical for skin barrier functions. It is known that reduced FLG expression causes skin barrier dysfunctions and results in atopic dermatitis (AD). Restoring FLG expression therefore may serve as an effective therapeutic strategy against AD. Using normal human epidermal keratinocyte (NHEK), we identified a phenylalanine amide derivative, termed Compound 8.1, that promotes expression of FLG and other skin barrier-related genes in NHEKs. Gene expression profiling by microarray suggested that Compound 8.1 promotes FLG expression through activation of the aryl hydrocarbon receptor (AHR). Interestingly, compared to a typical AHR activator, FICZ (6-Formylindolo[3,2-b]carbazole), Compound 8.1 preferentially upregulated the expression of genes related to keratinocyte differentiation and skin barrier function in an AHR-dependent manner, but induced a conventional AHR target gene involved in cellular toxicity, CYP1A1, to a significantly lesser extent. Structure-activity relationship analysis further demonstrates that the structural modification of Compound 8.1 could dissociate induction of skin barrier-related gene expression from CYP1A1-dependent metabolism of xenobiotics in AHR actions. Together, our results suggest that Compound 8.1 serves as a prototype compound for developing novel AHR-activating drugs to treat skin barrier dysfunctions without toxicity.