GSK621, a new thienopyridone deritate, is specific activator of AMPK that can activate ACC (S79) and ULK1 (S555) in MOLM-14 cells with IC50 of 30 μM[2]. GSK621 could induce cytotoxicity (with a median IC50 of 20 µM) by activating autophagy independent of mTORC1. Moreover, the researchers also found that AMPK activation and constitutive activation of the mTORC1 signaling pathway have a lethal interaction in a series of AML primary samples and cell lines, while constitutively activated mTORC1 is absent in normal hematopoietic progenitors, so AMPK activation does not cause toxic effects on normal cells[2]. There are also study demonstrate that GSK621 also can inhibit human melanoma cells A375 survival in both time- and concentration-dependent (1 μM – 3 μM) manners as well as pro-apoptotic activity[3]. In vivo, GSK621 (30 mg/kg twice daily) decreased leukemia growth and significantly prolonged survival of xenograft tumor mouse[4]. On the other hand, the oral administration of GSK621 inhibited the LPS-induced TNFα production and endotoxin shock in BALB/c mice[5].
搜索
