| 1 | In vitro: GSK2981278 markedly and potently inhibits IL-17A and IL-22 protein
secretion in a concentration dependent manner (IC50 = 3.2 nM) during 5
days of culture under Th17 skewing conditions.GSK2981278 (0.3, 1, 3, 10,
30, 100, 300, 1000 pM; 5 day) potently and selectively inhibits IL-17
and IL-22 levels. Culture in the presence of ≥3 nM GSK2981278 led to a
near-complete inhibition of IL-17A protein secretion.
Reference: Development of a Topical Treatment for Psoriasis Targeting RORγ: From Bench to Skin. PLoS One. 2016 Feb 12;11(2):e0147979. |
| 2 | In vivo: The imiquimod (IMQ) mouse model was employed to demonstrate efficacy
of GSK2981278 in a psoriaform-like mouse model. Topical application of
IMQ can induce and exacerbate psoriasis-like chronic skin inflammation
in mice, including epidermal thickening, a dependence on T cell
immunity, and a mechanism dependent on the IL-23/IL-17 pathway. It was
first confirmed that GSK2981278 can inhibit IL-17A protein secretion by
mouse CD4+ T cells, confirming cross-reactivity of our compound for both
mouse and human RORγ (data not shown). Next, mice were treated
topically with GSK2981278 (1% ointment or placebo) for three days (day
-3 to day 0), after which mice continued to receive compound for the
duration of the study. Starting on day 0, mice were challenged topically
with IMQ (5%) cream or petrolatum (non-inflammatory inert cream) for up
to ten days (day 0 to day +9). On the last day of treatment, the skin
was imaged and clinically assessed. GSK2981278 was undetectable (<5
ng/ml) in serum at harvest, indicating that systemic exposure was
minimal. Mice exposed to GSK2981278 exhibited reduced skin redness and
scaling, as well as decreased hyperplasia, as evidenced by a 23%
reduction in epidermal thickness when compared to the placebo +
IMQ-treated group (Fig 2A and 2B).
Reference: Development of a Topical Treatment for Psoriasis Targeting RORγ: From Bench to Skin. PLoS One. 2016 Feb 12;11(2):e0147979. |
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