Ceralasertib(AZD6738)

AZD6738 is a potent inhibitor of ATR kinase with an IC50 of 1 nM.

Signaling Pathways >> Cell Cycle/DNA Damage >> ATM/ATR

Signaling Pathways >> PI3K/Akt/mTOR >> ATM/ATR

Research Areas >> Cancer

ATR:1 nM (IC50)

PI3Kδ:6.8 μM (IC50)

DYRK:10.8 μM (IC50)

AZD6738 is a potent inhibitor of ATR kinase activity with an IC50 of 0.001 μM against the isolated enzyme and 0.074 μM against ATR kinase-dependent CHK1 phosphorylation in cells. 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[1]. AZD6738 inhibits human breast cancer cell lines with IC50 values less than 1 μM using MTT assay. AZD6738 induces cell cycle arrest and apoptosis. It downregulates DNA damage response molecules and cell proliferative signaling molecules[2].

Daily administration of AZD6738 and ATR kinase inhibition for 14 consecutive days is tolerated in mice and enhances the therapeutic efficacy of cisplatin in xenograft models. Remarkably, the combination of cisplatin and AZD6738 resolves ATM-deficient lung cancer xenografts[1].

AZD6738 is dissolved in DMSO at 30 mM and diluted in DMSO to desired working concentrations. The final DMSO concentration in media for all conditions and controls is 0.1% for AZD6738 dose response experiments, 0.05% for AZD6738 + chemotherapy viability experiments, and 0.025% for all experiments involving 0.3 μM and 1.0 μM doses of AZD6738[1].

Mice: AZD6738 is dissolved in DMSO at a concentration of 25 mg/mL or 50 mg/mL and diluted 1:5 in propylene glycol. AZD6738 is administered by oral gavage at 25 mg/kg (H23) or 50 mg/kg (H460) for 14 consecutive days. The dosing volume is 10 mL/kg.[1].

[1]. Vendetti FP, et al. 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.

[2]. Kim HJ, et al. Anti-tumor activity of the ATR inhibitor AZD6738 in HER2 positive breast cancer cells. Int J Cancer. 2017 Jan 1;140(1):109-119.

Wortmannin | Berzosertib (VE-822) | KU55933 (ATM Kinase Inhibitor) | VE-821 | AZD-0156 | KU 60019 | AZ20 | AZD1390 | CP-466722 | CGK 733 | ETP-46464 | KU 59403