Department of Chemistry, College of Natural Science, Inha University, Incheon 402-751, Republic of Korea.
Bioorg Med Chem Lett. 2010 Feb 1;20(3):1075-7. doi: 10.1016/j.bmcl.2009.12.033. Epub 2009 Dec 11.
In a previous study, protein tyrosine phosphatase 1B (PTP1B) inhibitors, SA18 and SA32, exhibited anti-obesity effects in a mouse model by suppressing weight gain and improving blood parameters, including free fatty acid (FFA) levels. In a separate study, depletion of the PTP1B gene in mice suppressed weight gain without significant change in FFA levels. The discrepancy in FFA concentrations between the two studies suggested that the in vivo target of the SA compounds might not be limited to PTP1B. In this study, SA18 and SA32 were found to be potent inhibitors of IkappaB Kinase-beta (IKK-beta). In vivo relevance of the inhibitory activity was evaluated in differentiated adipocytes. Inhibition of IKK-beta, in addition to inhibition of PTP1B, in mice treated with the SA compounds, could be a possible mechanism of the compound's biological response including the resistance to diet-induced weight gain and improvement in blood parameters. As potent and cell-permeable IKK-beta inhibitors, SA18 and SA32 could also be valuable in biological experiments.
在之前的研究中，蛋白酪氨酸磷酸酶 1B（PTP1B）抑制剂 SA18 和 SA32 通过抑制体重增加和改善血液参数（包括游离脂肪酸（FFA）水平），在肥胖小鼠模型中表现出抗肥胖作用。在另一项研究中，敲除小鼠的 PTP1B 基因可抑制体重增加，而 FFA 水平没有显著变化。这两项研究中 FFA 浓度的差异表明，SA 化合物的体内靶标可能不仅限于 PTP1B。本研究发现 SA18 和 SA32 是 IkappaB 激酶-β（IKK-β）的有效抑制剂。在分化的脂肪细胞中评估了体内抑制活性的相关性。IKK-β的抑制作用，除了 PTP1B 的抑制作用之外，在接受 SA 化合物治疗的小鼠中，可能是化合物生物学反应的一种可能机制，包括对饮食诱导的体重增加的抵抗力和血液参数的改善。作为有效的、细胞渗透性的 IKK-β抑制剂，SA18 和 SA32 也可能在生物学实验中具有重要价值。
