VE-821 is a novel ATR inhibitor. VE-821 was shown to inhibit ATR-mediated signalling in response to replication arrest induced by severe hypoxia. VE-821 inhibited radiation- and gemcitabine-induced phosphorylation of Chk1, confirming inhibition of ATR signaling. ATR inhibition by VE-821 led to inhibition of radiation-induced G 2/M arrest in cancer cells. Consistently, VE-821 significantly enhanced the sensitivity of PSN-1, MiaPaCa-2 and primary PancM pancreatic cancer cells to radiation and gemcitabine under both normoxic and hypoxic conditions. VE-821 induced DNA damage and consequently increased Ataxia Telangiectasia Mutated-mediated phosphorylation of H2AX and KAP1. Most importantly, VE-821 increased radiation-induced loss of viability in hypoxic conditions. Reduced cancer cell radiosurvival following treatment with VE-821 was also accompanied by increased DNA damage and inhibition of homologous recombination repair, as evidenced by persistence of γH2AX and 53BP1 foci and inhibition of Rad51 foci, respectively.
 |
Source | Radiat Oncol (2015). Figure 2. VE-821 |
| Method | Colonies assay | |
| Cell Lines | HeLa, U2OS, and 1BR-hTERT cells | |
| Concentrations | 1 μM | |
| Incubation Time | 8 h or 24 h | |
| Results | With 24-hour treatment of VE-821, HeLa and U2OS cells were significantly radiosensitized by both kinds of radiation, while little was observed in irradiated 1BR-hTERT cells by the inhibitor |
| Cell Experiment | |
|---|---|
| Cell lines | MiaPaCa-2, PSN-1 and Panc1 cells |
| Preparation method | Cell viability assays MiaPaCa-2, PSN-1 and Panc1 (5 x 104) were plated in 96-well plates and after 4 h treated with increasing concentrations of VE-821 at 1 h before irradiation with a single dose of 4 Gy. Medium was replaced 72 h post-irradiation at which point viability was measured using the using the Alamar Blue assay (Resazurin substrate, SIGMA). Cells were allowed to proliferate and cell viability was again analyzed at day 10 for the different treatment conditions. Cell viability and surviving fraction were normalized to the untreated (control) group. |
| Concentrations | 0~9µM |
| Incubation time | 72h |
| Animal Experiment | |
|---|---|
| Animal models | mice bearing PSN-1 xenografts |
| Formulation | 10% Vitamin E d-alpha tocopheryl polyethylene glycol 1000 succinate and administered by gavage, in 200 μl. |
| Dosages | 60 mg/Kg on days 0 and 1 |
| Administration | oral gavage |
| Molecular Weight | 368.41 |
| Formula | C18H16N4O3S |
| CAS Number | 1232410-49-9 |
| Solubility (25°C) | DMSO 60 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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