ETP-46464 is a potent inhibitor against mTOR, ATR, DNA-PK, PI 3-Kα and ATM with IC50 of 0.6, 14, 36, 170 and 545 nM, respectively. ETP-46464 preferentially suppresses radiation-induced cellular ATR activity (>90% at 500 nM) over ATM or DNA-PK activity (IC50 > 5 μM) in U2OS cells, while exhibiting much reduced or little potency toward a panel of 26 other kinases (>55% inhibition at 5 μM). ETP-46464 (10 μM) inhibited the UV-induced phosphorylation of CHK1 serine 317. Further, the phosphorylation of ATM serine 1981 was increased in cells incubated in 10 μM ETP-46464 and exposed to 10 J/m2 UV.
 |
Source | Gynecol Oncol (2015). Figure 3. ETP-46464 |
| Method | Immunoblot | |
| Cell Lines | Gynecologic carcinoma cells | |
| Concentrations | 5 μM | |
| Incubation Time | 3 h | |
| Results | The GYN cancer cell lines were treated at their respective LD50 levels of cisplatin alone or in combination with ATRi (5.0 μM ETP-46464) and/or ATMi (10.0 μM KU55933) for 3 h. Total ATR, ATM, Chk1 and Chk2 did not vary significantly under any of these treatment conditions. |
| Cell Experiment | |
|---|---|
| Cell lines | 23T, 239T, Calu6 and H460 cells line |
| Preparation method | Proliferation assays MTT Assay (Trevigen, Gaithersburg, MD) was used to measure cell proliferation. Drug combinations were evaluated using CalcuSyn (BIOSOFT, Ferguson, MO) software based on the multiple drug effect equation of Chou-Talalay. Experimental values were imputed into Calcusyn to calculate IC50 and a combination index (CI, a quantitative measure of the synergy (CI < 1), additivity (CI = 1), or antagonism (CI > 1) between drugs). Log-transformed CI’s are plotted against growth inhibition/effective dose (ED) with corresponding 95 % confidence intervals. Synergism is indicated when the 95 % CI falls below the x-axis (log CI = 0; CI = 1), whereas antagonism is indicated when the 95 % CI falls above the x-axis, at each respective region of the effective dose. |
| Concentrations | |
| Incubation time | 2 days |
| Animal Experiment | |
|---|---|
| Animal models | |
| Formulation | |
| Dosages | |
| Administration | |
| Molecular Weight | 470.52 |
| Formula | C30H22N4O2 |
| CAS Number | 1345675-02-6 |
| Solubility (25°C) | DMSO 6 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.
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