AZD6738 is an orally active, and selective ATR kinase inhibitor with IC50 of 1 nM. AZD6738 induces cell death and senescence in non-small cell lung cancer (NSCLC) cell lines. AZD6738 impairs viability of four Kras mutant cell lines: H23, H460, A549, and H358, with the lowest GI50 and greatest maximal inhibition in H460 and H23 cells (1.05 μM, 88.0% and 2.38 μM, 86.2%, respectively). AZD6738 potentiates the cytotoxicity of cisplatin and gemcitabine in NSCLC cell lines with intact ATM kinase signaling, and potently synergizes with cisplatin in ATM-deficient NSCLC cells.
In vivo: In nude mice bearing H460 and H23 tumors, AZD6738 (50 mg/kg, p.o.) results in tumor growth inhibition (TGI), and the the combination with cisplatin causes rapid regression of ATM-deficient H23 tumors. In nude mice bearing LoVo xenografts, a combination of AZD6738 (50 mg/kg) + IR (2 Gy) avoids toxicity while still maintaining efficacy.
|Source||Oncotarget (2015 Dec). Figure 5. AZD6738|
|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.|
|Source||Sci Rep (2015 Aug). Figure 6. AZD6738|
|Method||multi-parametric cell based assays|
|Cell Lines||LoVo cells|
|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 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.|
|Incubation time||48 h|
|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|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 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 resveratrol of 11.2 mg/kg.
|Solubility||DMSO: 80 mg/mL
Ethanol: 40 mg/mL warmed
Anti-tumor activity of the ATR inhibitor AZD6738 in HER2 positive breast cancer cells.
Kim HJ, et al. Int J Cancer. 2017 Jan 1;140(1):109-119. PMID: 27501113.
The orally active and bioavailable ATR kinase inhibitor AZD6738 potentiates the anti-tumor effects of cisplatin to resolve ATM-deficient non-small cell lung cancer in vivo.
Vendetti FP, et al. Oncotarget. 2015 Dec 29;6(42):44289-305. PMID: 26517239.
Synthetic lethality in chronic lymphocytic leukaemia with DNA damage response defects by targeting the ATR pathway.
Kwok M, et al. Lancet. 2015 Feb 26;385 Suppl 1:S58. PMID: 26312880.
Bridging the gap between in vitro and in vivo: Dose and schedule predictions for the ATR inhibitor AZD6738.
Checkley S, et al. Sci Rep. 2015 Aug 27;5:13545. PMID: 26310312.
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