AZD7762 | Checkpoint kinase 1/2 inhibitor

AZD7762 (860352-01-8, free base) is a potent and selective inhibitor of checkpoint kinases 1 and 2 (IC₅₀ = 5 nM for both).¹ It abrogates DNA damage-induced S and G2 checkpoints and enhances the efficacy of DNA damaging agents such as gemcitabine and irinotecan. AZD7762 also enhanced the radiation sensitivity of p53-mutant tumor cell lines.^2,3 AZD7762 was able to overcome imatinib resistance in CML cells.⁴ AZD7762 has also been reported to be a potent inhibitor of MEKK2 (MAP3K2) – IC₅₀ = 20 nM.⁵ It has also recently been shown to inhibit antigen-stimulated degranulation from RBL-2H3 (IC₅₀ = 28 nM) and BMMCs (IC₅₀ = 99 nM) as well as suppressing degranulation of LAD2 human mast cells (IC₅₀ = 50 nM) via Syk suppression through inactivation of Lyn and Fyn kinases.⁶

References/Citations:

1) Zabludoff et al. (2008) AZD7762, a novel checkpoint kinase inhibitor, drives checkpoint abrogation and potentiates DNA-targeted therapies; Mol. Cancer Ther. 7 2955
2) Mitchell et al. (2010) In vitro and in vivo radiation sensitization of human tumor cells by a novel checkpoint kinase inhibitor, AZD7762; Clin. Cancer Res. 16 2076
3) Morgan et al. (2010) Mechanism of radiosensitization by the Chk1/2 inhibitor AZD7762 involves abrogation of the G2 checkpoint and inhibition of homologous recombinational DNA repair; Cancer Res. 70 49721
4) Lei et al. (2018) Chk1 inhibitors overcome imatinib resistance in chronic myeloid leukemia cells; Leuk. Res. 64 17
5) Ahmad et al. (2015) Identification of Ponatinib and Other Known Kinase Inhibitors with Potent MEKK2 Inhibitory Activity; Biochem. Biophys. Res. Commun. 463 888
6) Park et al. (2018) Repositioning of anti-cancer drug candidate, AZD7762, to an anti-allergic drug suppressing IgE-mediated mast cells and allergic responses via the inhibition of Lyn and Fyn; Biochem. Pharmacol. 154 270