GSK2636771 is a potent and selective, orally bioavailable inhibitor of phosphatidylinositol 3-kinase-beta (PI3Kβ) for the treatment of PTEN deficient tumors. GSK2636771 shows selectively inhibitory activity in PTEN null cell lines (human prostate adenocarcinoma PC-3 and breast cancer HCC70) with EC50 of 36 nM and 72 nM, respectively. GSK2636771 decreases phosphorylated protein kinase Akt (Ser473) levels in these xenograft models. GSK2636771 (100 mg/kg) do not increase glucose/insulin levels in mice. GSK2636771 is currently in Phase I/II trials.
|Cell lines||EEC cell lines|
|Preparation method||Cells were plated in 96-well microtiter plates at densities ranging from 1,500 to 15,000 cells/ well, optimized for untreated control cells to be 80-90% confluent at the endpoint of the experiment. After 24h, cells were treated with serial dilutions (100pM to 10μM) of PI3K and MAPK pathway inhibitors (Supplementary Methods, Supplementary Table 3). Cell viability was assessed after 72h of treatment by incubation with CellTiter Blue (Promega, Southampton, UK) for 1.5h.|
|Concentrations||100pM to 10μM|
|Animal models||6- to 8-week-old female athymic nude mice BT474 tumor model|
|Formulation||GSK2636771 was dissolved on 0.5% metilcellulose and 0.2% Tween 80.|
|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 80 mg/mL|
|Source||Cancer Cell (2015). Figure 3. GSK2636771 (Abmole)|
|Method||Tumor growth assay|
|Concentrations||30mg/kg per oral gavage daily|
|Incubation Time||21 days|
|Results||Both BYL719 and GSK2636771, a structurally unrelated p110b inhibitor currently in clinical trials, slowed tumor growth but only the combination induced tumor shrinkage.|
|Source||Cancer Cell (2015). Figure 3.GSK2636771 (Abmole)|
|Cell Lines||BT-474, SKBR3 cell|
|Incubation Time||24 h|
|Results||This led to the loss of p110b recruitment and the block of the rebound of AKT activation observed 24 hr after treatment with BYL719 alone.|
Cancer Cell. 2015 Jan 12;27(1):97-108.
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