GSK2981278 is a RORγ-selective inverse agonist.
RAR-related orphan receptor gamma (RORγ) is a protein that in humans is encoded by the RORC gene. The RORγ protein is a DNA-binding transcription factor and is a member of the NR1 subfamily of nuclear receptors.
In vitro: Previous study found that GSK2981278 had no significant effect on RORα-dependent activation, indicating its selectivity for RORγ. GSK2981278 also demonstrated 10-fold greater potency for IL-17A inhibition than its analogs of GSK3038548 and GSK3038549. In addition, authors examined the effect of GSK2981278 on endogenous il17a expression in Jurkat cells. Results showed that GSK2981278 could repress the activation of il17a by RORγt in a dose-responsive manner [1].
In vivo: In previous study, the imiquimod (IMQ) mouse model was employed to demonstrate efficacy of GSK2981278 in a psoriaform-like mouse model. Results showed that the topical application of IMQ could induce and exacerbate psoriasis-like chronic skin inflammation in mice. Next, mice were treated topically with GSK2981278 for three days, after which mice continued to receive compound for the duration of the study. It was found that GSK2981278 was undetectable in serum at harvest, suggesting that systemic exposure was minimal. In addition, mice exposed to GSK2981278 exhibited reduced skin redness and scaling, as well as decreased hyperplasia [1].
Clinical trial: The study of safety and efficacy of topical GSK2981278 ointment in plaque psoriasis has been finished but there is no results released [2].
References:
[1] Smith SH et al. Development of a Topical Treatment for Psoriasis Targeting RORγ: From Bench to Skin. PLoS One. 2016 Feb 12;11(2):e0147979.
[2] https://clinicaltrials. gov/ct2/show/NCT02548052 term=GSK2981278&rank=2