Description
ZSTK474 can inhibit PI3K-gamma with IC50 of 6 nM.
Storage
2 years at -20centigrade Powder
Molecular Formula
C19H21F2N7O2
Chemical Name
2-(difluoromethyl)-1-(4,6-dimorpholino-1,3,5-triazin-2-yl)-1H-benzo[d]imidazole
Solubility
DMSO 21 mg/mL Water
In vitro
ZSTK474, as a novel s-triazine derivative, can inhibit PI3K-gamma with IC50 of 6 nM by binding to the ATP-binding pocket of PI3K. PI3Kdelta was inhibited most potently by ZSTK474 with a Ki of 1.8 nM. ZSTK474 inhibited phosphorylation of signaling components downstream from PI3K, such as Akt and glycogen synthase kinase 3beta. ZSTK474 also suppressed the expression of nuclear cyclin D1 and Ki67, both of which are hallmarks of proliferation and induced marked G(0)/G(1) arrest, but did not increase the subdiploid cells or activate caspase, both of which are hallmarks of apoptosis.Comapring to LY294002, ZSTK474 directly inhibited PI3K activity more efficiently than the PI3K inhibitor LY294002.
In vivo
ZSTK474 administered orally to mice had strong antitumor activity against human cancer xenografts and ZSTK474 reduce the level of Akt phosphorylation in xenograft tumors. ZSTK474 significantly inhibited tumour growth in the RXF-631L xenograft model. ZSTK474 significantly reduced number of microvessels in the ZSTK474-treated mice, suggesting the highly promising antiangiogenic activity in vivo. In human umbilical vein endothelial cells (HUVECs), submicromolar concentrations of ZSTK474 inhibited cell growth, blocked VEGF-induced cell migration and the tube formation, and thus revealed potent in vitro antiangiogenic activity. ZSTK474 treatment also inhibited the expression of HIF-1alpha and secretion of VEGF.
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