Inhibition of IκB Kinase β (IKKβ) and Anti-diabetic Effect of SA51

Abstract

SA51, a medium potency inhibitor of protein tyrosine phosphatase 1B (PTP1B), was identified to be a potent inhibitor of IκB kinase β (IKKβ). Consistent with this, SA51 prevented lipopolysaccharide (LPS)-induced breakdown of IκBα in macrophages. The effects of SA51 in mice were compared with those of structurally related compounds, SA18 and SA32, which were previously reported as inhibitors of both enzymes -less potent against IKKβ but more potent against PTP1B compared to SA51. SA51 improved glucose tolerance and lipid parameters in mice, consistent with the results reported for IKKβ +/− mice. In contrast, SA18 and SA32 showed anti-obesity effects without anti-diabetic effects. Collectively, the effects of SA51 could be due largely to the inhibition of IKKβ, whereas SA18 and SA32 may be more likely to inhibit PTP1B, consistent with their relative in vitro inhibitory effects.

Antiobesity Effect of SA37 in High‐Fat Diet‐induced Obese C57BL/6J Mice

“…The enzyme activity was measured as described previously using a commercial kit (Cell Signaling Technology, Danvers, MA, USA) and time‐resolved fluorescence . Briefly, IKKβ and inhibitor in the reaction buffer were incubated for 10 min at 30 °C before the reaction was initiated by adding substrate (a biotinylated peptide containing residues surrounding Ser32 of IκB‐α) and ATP.…”

“…Animal weights were recorded every 3 or 4 days. Glucose tolerance test (GTT) was performed after the 4 weeks of drug administration as previously described . Briefly, 6 h fasted mice were injected intraperitoneally with 1.0 g/kg glucose at time zero.…”