Sapanisertib (INK 128) is an orally bioavailable inhibitor of raptor-mTOR (TOR complex 1 or TORC1) and rictor-mTOR (TOR complex 2 or TORC2) with potential antineoplastic activity.

PI3Kδ:230 nM, PI3Kγ:221 nM, mTOR:1.4 nM(Ki), PI3Kα:219 nM

每日给多种移植体模型中口服给药INK 128,抑制血管生成和肿瘤生长.每天给ZR-75-1乳腺癌异种移植模型用0.3 mg/kg INK 128处理显示对肿瘤生长的抑制效果.

INK 128作为TORC1/2抑制剂,抑制TORC1的下游底物S6和4EBP1的磷酸化,并选择性抑制TORC2下游底物Ser473上的AKT磷酸化。INK 128对mTOR表现出酶抑制活性,对PI3K激酶的选择性高100倍以上。此外,INK 128还对雷帕霉素和pan-PI3K抑制剂耐药的细胞系显示出有效的抑制作用。

mTOR activity is assayed using LanthaScreen Kinase kit reagents. PI(3)K α, β, γ and δ activity are assayed using the PI(3)K HTRF assay kit. The concentration of INK128 necessary to achieve inhibition of enzyme activity by 50% (IC50) is calculated using concentrations ranging from 20 μM to 0.1 nM (12-point curve). IC50?values are determined using a nonlinear regression model.

PC3 cells are treated with the appropriate drug for 48 h, and proliferation is measured using CellTiter-Glo Luminescent reagent. The concentration of INK128 necessary to achieve inhibition of cell growth by 50% (IC50) is calculated using concentrations ranging from 20.0 μM to 0.1 nM (12-point curve).