货号：W2216

储存条件：粉末-20°C可保存3年；液体-80°C可保存12月。

产品描述

Phosphoinositide-3-kinase family (PI3Ks) phosphorylates PtdIns (Phosphatidylinositol), PtdIns4P (Phosphatidylinositol 4-phosphate) and PtdIns(4,5)P2 (Phosphatidylinositol 4,5-bisphosphate) to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3). PIP3 plays a key role in recruiting PH domain-containing proteins to the membrane, including AKT1 and PDPK1, activating signaling cascades involved in cell growth, survival, proliferation, motility and morphology. KY-12420, also termed wortmannin, is a PI3K inhibitor. The IC50 value of KY-12420 against PI3K was 3 nM according to purified calf PI3K assay or cell based immunoprecipitate assay. In intact cells, KY-12420 inhibited PI3K activity with an IC50 of 2 nM. Post 24 h incubation, KY-12420 could sensitize melanoma cell lines A375, Mel-HO, as well as respective TRAIL resistant cell lines, for TRAIL-induced apoptosis at the concentrations of 4 μM or 8 μM, as revealed by a sub-G1 cell analysis, while KY-12420 alone was not effective. In lung cancer cell lines A549 and H1703, KY-12420 at the concentration of 2.5 μM also enhanced cytotoxicity induced by tamoxifen. In an orthotopic pancreatic tumor model established by injection of PK1 cells into the pancreas of SCID mice, KY-12420 plus gemcitabine was administrated via i.p. injection. The dose of KY-12420 was 0.35 mg/kg and the dose of gemcitabine was 80 mg/kg. Both of the agents were injected biweekly for a total treatment period of 5 weeks. The result turned out that KY-12420 plus gemcitabine reduced tumor weights by 5-fold relative to the vehicle control. For comparison, the group of gemcitabine alone at the same dose and schedule reduced tumor weights by 1.4-fold, and the group of KY-12420 alone failed to inhibit tumor growth.

作用机制

Based on the X-ray crystallographic structure of KY-12420 bound to PI3Kγ in the kinase’s ATP binding pocket, KY-12420 most closely fits and fills the active site and induces a conformational change in the catalytic domain of the kinase.

产品信息