KU-55933 is a cell-permeable, potent, selective and ATP-competitive inhibitor of ATM (Ataxia telangiectasia mutated), a serine/threonine protein kinase, that exhibits an IC50 of 13 nmol/L and a Ki of 2.2 nmol/L. KU-55933 shows specificity with respect to inhibition of other phosphatidylinositol 3'-kinase-like kinases. Cellular inhibition of ATM by KU-55933 was demonstrated by the ablation of ionizing radiation-dependent phosphorylation of a range of ATM targets, including p53, gammaH2AX, NBS1, and SMC1. KU-55933 did not show inhibition of UV light DNA damage induced cellular phosphorylation events. Exposure of cells to KU-55933 resulted in a significant sensitization to the cytotoxic effects of ionizing radiation and to the DNA double-strand break-inducing chemotherapeutic agents, etoposide, doxorubicin, and camptothecin. Inhibition of ATM by KU-55933 also caused a loss of ionizing radiation-induced cell cycle arrest. By contrast, KU-55933 did not potentiate the cytotoxic effects of ionizing radiation on ataxia-telangiectasia cells, nor did it affect their cell cycle profile after DNA damage. We conclude that KU-55933 is a novel, specific, and potent inhibitor of the ATM kinase.
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Source | J Neurooncol (2012). Figure 2. KU-55933 |
| Method | clonogenic assay | |
| Cell Lines | U251 and U87 malignant glioma cell lines | |
| Concentrations | 10 microM | |
| Incubation Time | 24 hours or 72 hours | |
| Results | U87 cells also were sensitized by KU-55933 treatment, although the extent of sensitization was less profound |
| Cell Experiment | |
|---|---|
| Cell lines | LU1205 and WM35 cells |
| Preparation method | Apoptosis studies. Cells were exposed to soluble TRAIL (50 ng/mL) alone or in combination with cycloheximide (2 μg/mL). Different variants of combined treatment were used, including γ-irradiation (5 Gy), in the presence or absence of specific inhibitors of signaling pathways followed by TRAIL treatment. Apoptosis was then assessed by quantifying the percentage of hypodiploid nuclei using fluorescence-activated cell sorting analysis. |
| Concentrations | 10 μM |
| Incubation time | 48 h |
| Animal Experiment | |
|---|---|
| Animal models | LU1205 cells Human melanoma transplant in nude mice. |
| Formulation | DMSO |
| Dosages | 10 μM |
| Administration | |
| Molecular Weight | 395.49 |
| Formula | C21H17NO3S2 |
| CAS Number | 587871-26-9 |
| Solubility (25°C) | DMSO 39 mg/mL |
| Storage |
Powder -20°C 3 years ; 4°C 2 years In solvent -80°C 6 months ; -20°C 1 month |
| Species | Mouse | Rat | Rabbit | Guinea pig | Hamster | Dog |
| Weight (kg) | 0.02 | 0.15 | 1.8 | 0.4 | 0.08 | 10 |
| Body Surface Area (m2) | 0.007 | 0.025 | 0.15 | 0.05 | 0.02 | 0.5 |
| Km factor | 3 | 6 | 12 | 8 | 5 | 20 |
| Animal A (mg/kg) = Animal B (mg/kg) multiplied by | Animal B Km |
| Animal A Km |
For example, to modify the dose of Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 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 Compound A of 10 mg/kg.
| Related ATM/ATR Products |
|---|
| Lartesertib
Lartesertib (M4076) is a potent inhibitor of serine/threonine protein kinase ATM. |
| KU-60019
KU-60019 is an improved ATM kinase-specific inhibitor with IC50 of 6.3 nM. |
| Elimusertib hydrochloride
Elimusertib (BAY 1895344) hydrochloride is a potent, orally active and selective ATR inhibitor with an IC50 of 7 nM. |
| Gartisertib
Gartisertib (VX-803) is an ATP-competitive, orally active, selective ATR inhibitor with Ki<150 pM. Gartisertib inhibits atR-driven phosphorylation of checkpoint kinase-1 (Chk1) with an IC50 value of 8 nM. It has antitumor activity. |
| Camonsertib (RP-3500)
Camonsertib (RP-3500) is an orally potent, selective ATR kinase inhibitor (ATRi) in biochemical assays IC50 1.00 nM. The RP-3500 is 30 times more selective to ATR (IC).50=120 nM), which is 2,000 times > ATM, DNA-PK, and PI3Kα kinase. |
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