Ceralasertib (AZD6738) is an orally active, selective ATR kinase inhibitor with an IC50 of 1 nM. AZD6738 inhibits ATR kinase activity and impels cell viability. AZD6738 induces rapid cell death in tumor cells with an ATM gene defect.
In vitro studies showed that AZD6738 inhibited ATR kinase activity and impaired cell activity in four Kras mutant cell lines H23, H460, A549 and H358. In ATM deficient H23 cells, AZD6738 strongly enhanced the effect of cisplatin on rapid cell death. In cells with p53 or ATM deletion, AZD6738 treatment causes replication fork stagnation and accumulation of unrepaired DNA damage, leading to mitosis disorder and thus cell death.
In vivo studies, AZD6738 (50 mg/kg, P.O.) induced tumor growth inhibition (TGI) in nude mice burdened with H460 and H23 tumors, and combined with cisplatin induced rapid degeneration of ATM-deficient H23 tumors. The combination of AZD6738 (50 mg/kg)+IR (2 Gy) in nude mice loaded with LoVo xenografts avoided toxicity while maintaining efficacy.
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Source | Oncotarget (2015 Dec). Figure 5. AZD6738 |
| Method | Western blot | |
| Cell Lines | H460 and A549 cells | |
| Concentrations | 0.3 or 1.0 μM | |
| Incubation Time | 48 hour | |
| Results | In H460 shATM cells, 1.0 μM AZD6738 shifted cisplatin IC50 from 2.77 μM to 0.22 μM (12.59-fold), compared to 2.36 μM to 0.43 μM (5.44-fold) and 1.83 uM to 0.84 (2.18-fold) in wildtype and scrambled control cells, respectively. Similar results were seen in A549 shATM cells. Treatment with 1.0 μM AZD6738 reduced cisplatin IC50 from 19.84 μM to 1.02 μM (19.45-fold) versus reductions from 7.79 μM to 2.61 μM (2.98-fold) and 9.68 μM to 3.48 μM (2.78- fold) in wildtype and scrambled control cells, respectively. Treatment with 0.3 μM AZD6738 also resulted in greater shifts in cisplatin IC50 and lower net IC50 values in shATM cell lines compared to wildtype and scrambled control lines. |
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Source | Sci Rep (2015 Aug). Figure 6. AZD6738 |
| Method | multi-parametric cell based assays | |
| Cell Lines | LoVo cells | |
| Concentrations | 80 mg/kg | |
| Incubation Time | 3 weeks | |
| Results | From tumor volume simulations an efficacious starting dose of 80 mg/kg AZD6738 was identified, providing clinicians with an indication of the expected rate of tumor regression and recovery. |
| Cell Experiment | |
|---|---|
| Cell lines | H23, H460, A549, and H358 cells |
| Preparation method | Cells are treated in white walled, clear bottom 96-well plates with the indicated doses of AZD6738, cisplatin, gemcitabine, or combination for 48 h. ATP levels are assessed as surrogate measure of viability is assessed using the CellTiter-Glo Luminescent Cell Viability Assay and Safire2 plate reader. Raw data are corrected for background luminescence prior to further analysis. For AZD6738 treatment, log dose response curves are generated in GraphPad Prism 6 by nonlinear regression (log(inhibitor) vs. response with variable slope) of log-transformed (x = log(x)) data normalized to the mean of untreated controls. GI50 values, defined as the dose X at which Y = 50%, were extrapolated from dose response curves. |
| Concentrations | ~30 μM |
| Incubation time | 48 h |
| Animal Experiment | |
|---|---|
| Animal models | Female athymic nude mice bearing H23 or H460 xenografts |
| Formulation | 10% DMSO, 40% propylene glycol, and 50% sterile dH2O |
| Dosages | 25 or 50 mg/kg |
| Administration | p.o. |
| Molecular Weight | 412.51 |
| Formula | C20H24N6O2S |
| CAS Number | 1352226-88-0 |
| Solubility (25°C) | DMSO: 70 mg/mL Ethanol: 40 mg/mL warmed |
| 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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ATR-IN-29 is a potent and orally active ATR kinase inhibitor with an IC50 value of 1 nM. |
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