Tapinarof

Tapinarof is a therapeutic aryl hydrocarbon receptor-modulating agent (TAMA) that binds to and activates the aryl hydrocarbon receptor (AhR). AhR is a ligand-dependent transcription factor that regulates gene expression in a variety of cell types, including macrophages, T-cells, antigen-presenting cells, fibroblasts, and keratinocytes. Upon binding to its ligand, AhR heterodimerizes with AhR nuclear translocator (ARNT) to form a complex with a high affinity for DNA binding. The AhR-ligand/ARNT complex can then bind to the specific DNA recognition sites to transcribe AhR-responsive genes. Additionally, AhR also exerts its effect through other transcription factors such as the nuclear factor κB and nuclear factor erythroid 2-related factor 2 (Nrf2), a downstream product of AhR-induced transcription that has antioxidant properties.

Dysregulation of AhR is one of the hallmarks of psoriasis, as psoriasis patients have a higher serum concentration of AhR compared to healthy individuals. Treatment of AhR ligands in vitro also results in a gene expression profile that is implicated in the pathogenesis of psoriasis. For instance, AhR activation causes the expansion and differentiation of Th17 and Th22, two major T cells responsible for releasing inflammatory cytokines IL-17 and IL-22.. Additionally, AhR activation also recruits persistent skin resident memory T cells, thus contributing to the chronicity of psoriasis. However, the specific binding of tapinarof to AhR modulates a unique set of genes that are dysregulated in psoriasis, distinctive from other AhR ligands. Further, tapinarof also induces barrier protein expression, such as filaggrin, hornerin, and involucrin, to restore the skin barrier and epidermal function and decrease oxidative stress. It is currently unknown why AhR ligands like tapinarof can reduce psoriatic inflammations in one setting but upregulate inflammatory genes in another setting.

It is possible that the anti-inflammatory effect of tapinarof as an AhR agonist might be due to Nrf2. Although Nrf2 is a known downstream effector of AhR, not all AhR agonists activate this pathway. For instance, 2,3,7,8-tetrachlorodibenzo-p-dioxin, an AhR agonist, does not show any antioxidant activity after AhR activation. Therefore, it is hypothesized that the dual AhR/Nrf2 action of tapinarof is essential to the effect of tapinarof in treating psoriasis.