Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan.
Eur J Pharmacol. 2010 Sep 10;642(1-3):177-82. doi: 10.1016/j.ejphar.2010.06.002. Epub 2010 Jun 17.
Lipid phosphatase SH2 domain-containing inositol 5'-phosphatase 2 (SHIP2) plays an important role in the regulation of insulin signaling. In this report, we identified AS1938909, a novel small-molecule SHIP2 inhibitor. AS1938909 showed potent inhibition of SHIP2 (Ki=0.44 microuM) and significant selectivity over other related phosphatases. Further, AS1938909 increased Akt phosphorylation, glucose consumption, and glucose uptake in L6 myotubes. Treatment of L6 myotubes with SHIP2 inhibitors for 48 h significantly induced expression of GLUT1 mRNA, but not that of GLUT4. These results suggest that pharmacological inhibition of SHIP2 activates glucose metabolism due, at least in part, to up-regulation of GLUT1 gene expression.
SH2 结构域含有肌醇 5′-磷酸酶 2（SHIP2）的脂质磷酸酶在胰岛素信号转导的调节中发挥着重要作用。在本报告中，我们鉴定了一种新型小分子 SHIP2 抑制剂 AS1938909。AS1938909对 SHIP2 表现出很强的抑制作用（Ki=0.44 微摩尔），对其他相关磷酸酶具有显著的选择性。此外，AS1938909可增加 L6 肌管中的 Akt 磷酸化、葡萄糖消耗和葡萄糖摄取。用 SHIP2 抑制剂处理 L6 肌管 48 小时可显著诱导 GLUT1 mRNA 的表达，但不诱导 GLUT4 mRNA 的表达。这些结果表明，SHIP2 的药理学抑制作用激活了葡萄糖代谢，至少部分原因是 GLUT1 基因表达的上调。
