KRN5 is a Nuclear factor of activated T cells 5 (NFAT5) suppressor, with an IC50 of 750 nM.
The plasma half-life of KRN5 is estimated at >8 h when KRN5 is administered orally, and the bioavailability (F%) after oral and intravenous administration was 15% in rats. The IC50 value of KRN5 is 0.75 μM as determined by NFAT5-dependent reporter assay in LPS-stimulated RAW 264.7 cells, suggesting that the in vitro NFAT5 inhibitory capacity can be maintained after chemical modification of KRN2 to KRN5. Moreover, KRN5 is less toxic than BBR as determined by a cytotoxicity assay, hERG K+ channel assay, cytochrome inhibition assay, and liver microsomal metabolic stability test. KRN5 at a concentration of 1 μM inhibits the expressions of NFAT5, IL-6, MCP-1, and GM-CSF, which are NFAT5 target molecules, in RAW264.7 macrophages stimulated with LPS[1].
It is found that oral feeding of KRN5 every other day for 3 weeks from day 21 dose-dependently mitigates arthritis severity. When compared to methotrexate, a commonly used DMARD, the efficacy of oral KRN5 at 60mg/kg is more potent in suppressing arthritis; a supra-therapeutic dose (5 mg/kg) of methotrexate is administered orally twice a week for the same experimental period. Of special interest, no side effects are noted throughout the course of our experiments. The concentration of serum anti-type II collagen IgG also significantly decrease in the sera of KRN5-treated mice. In parallel, TNF-α and IL-6 production by LPS-stimulated splenocytes are significantly lower in KRN5-treated CIA mice than in vehicle-treatedmice. NFAT5 expression in spleen cells stimulated by LPS is also reduced by KRN5[1].
[1]. Han EJ, et al. Suppression of NFAT5-mediated Inflammation and Chronic Arthritis by Novel κB-binding Inhibitors. EBioMedicine. 2017 Apr;18:261-273.