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KU-60019
本产品不向个人销售,仅用作科学研究,不用于任何人体实验及非科研性质的动物实验。
KU-60019图片
CAS NO:925701-49-1
规格:≥98%
包装与价格:
包装价格(元)
2mg电议
5mg电议
10mg电议
25mg电议
50mg电议
100mg电议
250mg电议
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产品介绍
理化性质和储存条件
Molecular Weight (MW)547.67
FormulaC30H33N3O5S
CAS No.925701-49-1
Storage-20℃ for 3 years in powder form
-80℃ for 2 years in solvent
Solubility (In vitro)DMSO: 18 mg/mL (32.9 mM)
Water: <1 mg/mL
Ethanol: <1 mg/mL
SMILESO=C(NC1=CC(CC2=C(C(C3=CC(C=C(N4CCOCC4)O3)=O)=CC=C2)S5)=C5C=C1)CN6C[C@H](C)O[C@H](C)C6
SynonymsKU60019; KU 60019; KU-60019
实验参考方法
In Vitro

In vitro activity: Compared to KU-55933, KU-60019 is an improved more water-soluble inhibitor of the ATM kinase, while displaying similar target selectivity. KU-60019 has little activity against DNA-PKcs and ATR with IC50 values of 1.7 μM and>10 μM, respectively, as well as 229 other protein kinases such as PI3K, mTOR and mTOR/FKBP12. KU-60019 displays 3- to 10-fold more potency than KU-55933 at blocking radiation-induced phosphorylation of key ATM protein targets such as p53, γ-H2AX, and CHK2, in human glioma U87 and U1242 cells, as 1 μM of KU-60019 significantly induces>70% decrease of p53 (S15) phosphorylation to which extent ~10 μM of KU-55933 is required to achieve. KU-60019 effectively radiosensitizes human glioma cells with dose-enhancement ratio of 1.7 and 4.4 at 1 μM and 10 μM, respectively, and also radiosensitizes the normal fibroblasts but not the A-T fibroblasts. KU-60019 treatment (3 μM) blocks basal and insulin-induced AKT S473 phosphorylation by 70% and ~50%, respectively, and completely reduces radiation-induced AKT phosphorylation below the level of control. The effect of KU-60019 on AKT S473 phosphorylation can be seen in glioma cell lines and normal fibroblasts but not in A-T (h-TERT) cells, and can be significantly blocked by phosphatase inhibitor okadaic acid, suggesting a critical role of ATM kinase in regulating AKT phosphorylation via unknown phosphatase. Consistent with the inhibition of prosurvival AKT signaling, KU-60019 at 3 μM significantly inhibits migration and invasion of human glioma U87 cells by>70% and ~60%, respectively, as well as U1242 cells by>50% and ~60% respectively.


Kinase Assay: KU-55933 has an IC50 of 13 nM and Ki of 2.2 nM in vitro and is highly specific for the ATM kinase using a panel of 60 protein kinases. KU-60019 is an improved inhibitor of the ATM kinase with an IC50 of 6.3 nM, approximately half that of KU-55933. The IC50 values for DNA-PKcs and ATR are 1.7 and>10 μM, respectively, almost 270-and 1600-fold higher than for ATM. KU-60019 is 10-fold more effective than KU-55933 at blocking radiation-induced phosphorylation of key ATM targets in human glioma cells. In human U87 glioma cells, KU-55933 completely inhibits phosphorylation of p53 (S15) at 10 μM but not at 3 μM, whereas γ-H2AX levels are only partly reduced with 10 μM 1 h after irradiation. By comparison, 3 μM KU-60019 completely inhibits p53 phosphorylation and partial inhibits at 1 μM.


Cell Assay: Cells (U87 and U1242) are exposed to KU-60019 for 1, 3, and 5 days. Cell growth is determined by AlamarBlue. AlamarBlue is added to the medium to the recommended final concentration. Plates are incubated for 1 hour at 37 °C, fluorescence is determined on a Fluoro-Count plate reader (excitation 530 nm, emission 590 nm), and values are taken as a measure of cell growth. Cell survival is determined by trypan blue/fluorescence activated cell sorting (FACS) assay.

In VivoSuppression of ATM-dependent STAT3 activation by KU-55933 enhances TRAIL-mediated apoptosis through up-regulation of surface DR5 expression, whereas suppression of both STAT3 and NF-κB appeares to be involved in down-regulation of cFLIP accompanied by an additional increase in apoptotic levels. The ATM inhibitor KU-55933 affectes TRAIL-mediated apoptosis more strongly than the JAK2 inhibitor, AG490, or overexpression of STAT3β.
Animal modelAthymic female mice harboring orthotopic glioma U1242/luc-GFP tumors or human glioma U1242/luc-GFP tumors
Formulation & DosageDissolve in saline; KU-60019 (10 μM) is delivered at a rate of 0.5 μL/h by osmotic pump; KU-60019 (250 μM) in 12.5 μL is infused by CED; Administered intratumorally by convection-enhanced delivery or osmotic pump
ReferencesMol Cancer Ther. 2009 Oct;8(10):2894-902; Clin Cancer Res. 2013 Jun 15;19(12):3189-200.