Phosphoinositide 3-kinase (PI3-K) family members include p110α that is the most frequently mutated kinase in human cancer, and mTOR, which is a central regulator of cell growth and some other enzymes. PP242 exhibits potent selectivity for mTOR with IC50 of 8nM over other PI3K family kinases like p110α, p110β, p110γ, p110δ and DNA-PK with IC50 of 1.96μM, 2.2μM, 1.27μM, 0.102μM, and 0.408μM, respectively. In BT549 cells, PP242 treatment with concentration range 0.04-10μM inhibited the phosphorylation of Akt, the mTOR substrate p70S6K, and its downstream target S6 in a dose-dependent manner. PP242 potently inhibits PKCα with IC50 of 49nM. Low concentrations of PP242 inhibited the phosphorylation of Akt at S473 site, confirming that mTOR kinase activity was required for hydrophobic motif phosphorylation. Higher concentrations partially inhibited Akt T308-P in addition to S473-P, the effect of which on the phosphorylation of Akt in primary MEFs from embryos that lacked SIN1. PP242 was more effective to inhibit mTORC1 and inhibited the proliferation of primary MEFs, and the phosphorylation of 4EBP1 at T36/45 and S65. PP242 potently inhibited cap-dependent translation, by causing a higher level of binding between 4EBP1 and eIF4E, suggesting that cap-dependent translation will be more highly suppressed by PP242. After 8 h of treatment with PP242, no obvious effect on the morphology or abundance of actin stress fibers was found. Besides, PP242 had a dose-dependent effect on proliferation and at higher doses was much more effective at blocking cell proliferation. PP242 potently inhibited the proliferation of p190-transformed murine BM, SUP-B15, and K562 cells with GI50 of 12nM (cell growth was suppressed by 90%), 90 nM, and 85 nM, respectively, as well as inhibited the growth of solid tumor cell lines such as SKOV3 and U87 with GI50 of 0.49μM and 1.57μM, respectively. In adaptive immune function assays, PP242 had little effect at 1–10nM. While with increasing effects at 100nM and 1µM, the latter far exceeding its effective concentration for inhibiting growth in leukemia cell lines which also decreased the size of activated T cells.
Torkinib 细胞研究
细胞系
浓度
检测类型
检测时间
活动说明
数据源
3T3-L1
15 μM
Function Assay
4 h
suppresses expression of the Egr1 protein
25814662
786-O
0.1/0.5 μM
Function Assay
24 h
increases E-cadherin mRNA levels dose dependently
23147251
786-O
0-0.5 μM
Function Assay
24 h
results in a dose dependent increase in E-cadherin protein expression
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