GSK2126458 is a potent inhibitor of common activating mutants of p110α, p110β, p110γ, p110δ, mTORC1 and mTORC2 with Ki of 0.019 nM, 0.13 nM, 0.024 nM, 0.06 nM, 0.18 nM and 0.3 nM, respectively. PI3K, often overexpressed in cancer cells, plays a crucial role in tumor cell regulation and survival. GSK2126458 inhibited AKT signaling and it showed effects on p70S6K and rpS6 signaling with effects resembling those of rapamycin. PI3K inhibitor GSK2126458 causes a significant reduction in the levels of pAkt-S473 in T47D and BT474 cells with an IC50 of 0.41 nM and 0.18 nM, respectively. GSK2126458 leads to a G1 cell cycle arrest and produces the inhibitory effect on cell proliferation in a large panel of cell lines, including T47D and BT474 breast cancer lines with IC50 of 3 nM and 2.4 nM, respectively. GSK2126458 had a width of inhibitory activity for potent cell growth and induced cell death in various human tumor cells.
|Cell lines||BT474, HCC1954 and T-47D cells|
|Preparation method||BT474, HCC1954 and T-47D (human breast) were cultured in RPMI-1640 containing 10% fetal bovine serum at 37 in 5% CO2 incubator.Cells were then plated in 384 well black flat bottom polystyrene (Greiner #781086) in 48 µl of culture media per well at 1,000 cells/well. Following 72 hours of incubation with compounds each plate was developed and read. CellTiter-Glo reagent was added to assay plates using a volume equivalent to the cell culture volume in the wells.|
|Animal models||BT474 human tumor xenografts in mice|
|Dosages||0.3, 1 and 3mg/kg once daily for 5 days/week for 3 weeks|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
|Solubility||DMSO 100 mg/mL|
Discovery of GSK2126458, a Highly Potent Inhibitor of PI3K and the Mammalian Target of Rapamycin.
Knight SD, et al. ACS Med Chem Lett. 2010 Jan 19;1(1):39-43. PMID: 24900173.
[11C]GSK2126458 and [18F]GSK2126458, the first radiosynthesis of new potential PET agents for imaging of PI3K and mTOR in cancers.
Wang M, et al. Bioorg Med Chem Lett. 2012 Feb 15;22(4):1569-74. PMID: 22297110.
Comparison of the effects of the PI3K/mTOR inhibitors NVP-BEZ235 and GSK2126458 on tamoxifen-resistant breast cancer cells.
Leung E, et al. Cancer Biol Ther. 2011 Jun 1;11(11):938-46. PMID: 21464613.
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