Compound 401 is a potent inhibitor of DNA-PK (IC50=0.28 μM). Compound 401 is reported to be a poor inhibitor of PI3K, ATM, and ATR in vitro, but it is active against mTOR. Compound 401 shows activity against mTOR (IC50=5.3 μM) but not p110α/p85α PI3K (IC50>100 μM). Treatment of cells with Compound 401 blocks the phosphorylation of sites modified by mTOR-Raptor and mTOR-Rictor complexes (ribosomal protein S6 kinase 1 Thr389 and Akt Ser473, respectively). By contrast, there is no direct inhibition of Akt Thr308 phosphorylation, which is dependent on PI3K. Similar effects are also observed in cells that lack DNA-PK. Compound 401 inhibits immunoprecipitated epitope-tagged mTOR or endogenous mTOR in Raptor immunoprecipitates. In both cases, inhibition of 67% or 78% is obtained at 5 μM or 10 μM Compound 401, respectively. By contrast, dose response curves show that the p110α/p85α or p110β/p85α PI3K complexes are poorly inhibited by Compound 401 at these concentrations. The proliferation of TSC1-/- fibroblasts is inhibited in the presence of Compound 401, but TSC1+/+ cells are resistant.
|Cell lines||COS7 cells|
|Preparation method||Twenty-two hours later the cells were preincubated for 20 min with 0.1% dimethyl sulfoxide (Con) or the indicated concentrations of 401 (in μM).|
|Incubation time||22 h|
|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||6 mg/mL in DMSO|
Inhibition of mammalian target of rapamycin signaling by 2-(morpholin-1-yl)pyrimido[2,1-alpha]isoquinolin-4-one.
Ballou LM, et al. J Biol Chem. 2007 Aug 17;282(33):24463-70. PMID: 17562705.
|Related DNA-PK Products|
YU238259 is a novel inhibitor of homology-dependent DNA repair(HDR), but does not inhibit non-homologous end-joining (NHEJ), in cell-based GFP reporter assays.
LTURM34 is a specific DNA-PK inhibitor, 170-fold more selective for DNA-PK activity compared to PI3K activity, with IC50 value of 0.034 μM.
KU-0060648 is a dual inhibitor of DNA-PK and PI3Kα, PI3Kβ, PI3Kδ with IC50 of 8.6 nM and 4 nM, 0.5 nM, 0.1 nM respectively, less inhibition of PI3Kγ with IC50 of 0.59 μM.
NU7026 is a DNA-PK inhibitor with IC50 of 0.23 μM.
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