Lead optimization of aryl hydrocarbon receptor ligands for treatment of inflammatory skin disorders

Therapeutic aryl hydrocarbon receptor (AHR) modulating agents (TAMAs) gained attention in dermatology as non-steroidal anti-inflammatory drugs that improve skin barrier properties. By exploiting AHR’s known ligand promiscuity, we generated novel TAMAs by lead optimization of a selective AHR modulator (SAhRM; SGA360). Twenty-two newly synthesized compounds were screened yielding two novel derivatives, SGA360f and SGA388, in which agonist activity led to enhanced keratinocyte terminal differentiation. We questioned whether SGA derivatives can restore the disturbed epidermal differentiation processes that are known for the key AD-associated T helper-2 cytokine, interleukin-4 (IL-4). We performed genome-wide transcriptomic analysis by bulk RNA-sequencing after co-stimulation of human epidermal equivalents with interleukin-4 (IL-4; AD-HEE) and SGA360 (SAhRM activity), SGA360f or SGA388 (coupling of SAhRM to agonist activity), or TCDD (full AHR agonist). Comparative gene expression profiling using bulk RNA-seq for 3 biological replicate kertinocyte donors (PCK15, 16 and 33) either left untreated (control), treated with IL-4 or IL-4 in combination with SGA360, SGA360f, SGA388 or TCDD