Tapinarof (GSK2894512) is a naturally-derived small molecule produced by bacterial symbionts of entomopathogenic nematodes. Especially, Tapinarof displays significant efficacy in psoriasis and atopic dermatitis (AD) modls. Psoriasis vulgaris is a chronic autoimmune skin disorder resulting from interactions of genetic, environmental and systemic factors and affects 2-3% of the Caucasian population. AD is an intensely pruritic, chronic, relapsing, inflammatory skin disease. Also, the inflammatory response associated with AD is characterized by increased IgE production and Th2-associated cytokines and chemokines (eotaxin-3, IL-2, IL-4, IL-5, and IL-13). A study from Susan H Smith, et al. set out to determine the primary target through which tapinarof achieves its efficacy in these inflammatory skin conditions.

Firstly, the aryl hydrocarbon receptor (AhR) senses diverse endogenous and exogenous molecules and impacts multiple biological activities. And it exhibited as a critical regulator of innate and adaptive immune responses. And the compound impacts the balance of Th17 and Treg cells. Secondly, AhR activation modulates disease progression and antibacterial defense in multiple preclinical models of disease. AhR widely expresses in the skin and plays an important role in the development and maintenance of the skin barrier and the response to external environmental signals, including ultraviolet B exposure, dietary phytochemicals, environmental toxins and microbial products. What’s more, Despite a long history in toxicology, recent interest from immunologists and skin biologists have identified potential therapeutic benefits of the AhR pathway using various preclinical models.

Tapinarof activates the AhR pathway through direct binding.

It dose-dependently induces nuclear translocation of AhR in immortalized keratinocytes (HaCaT) (EC₅₀=0.16 nM).

Moreover, Tapinarof acts through AhR to reduce inflammation in IMQ-treated mice. AhR-sufficient mice on a C57Bl/6 background exhibit a reduced clinical score after treatment with Tapinarof or 6-formylindolo(3,2-b)carbazole (FICZ). In contrast, AhR KO mice do not respond to the anti-inflammatory effects of Tapinarof.

Reference:

Smith SH, et al. Tapinarof Is a Natural AhR Agonist that Resolves Skin Inflammation in Mice and Humans. J Invest Dermatol. 2017 Oct;137(10):2110-2119.