AZD-7762

AZD-7762 is a potent ATP-competitive checkpoint kinase (Chk) inhibitor in with IC₅₀ of 5 nM for Chk1. IC50 & Target: IC50: 5 nM (ChK1), 5 nM (ChK2)^[1] In Vitro: AZD-7762 (AZD7762) is an equally potent inhibitor of Chk1 and Chk2 in vitro. AZD-7762 potently inhibits Chk1 and Chk2, abrogates DNA damage-induced S and G₂ checkpoints, enhances the efficacy of gemcitabine and topotecan, and modulates downstream checkpoint pathway proteins. AZD-7762 potently inhibits Chk1 phosphorylation of a cdc25C peptide with an IC₅₀ of 5 nM as measured by a scintillation proximity assay. The K_i for AZD-7762 is determined to be 3.6 nM. Kinetic characterization suggests that AZD-7762 binds in the ATP-binding site of Chk1 and is thought to compete directly for ATP binding in a reversible manner. AZD-7762 is shown to abrogate the G₂ arrest induced by Camptothecin with an average EC₅₀ of 10 nM (n=12) and maximal abrogation in the range of 100 nM^[1]. In Vivo: In the rat H460-DNp53 xenograft study, AZD-7762 (AZD7762) potentiates the antitumor activity of Gemcitabine in a dose-dependent manner by a decrease in %T/C with increasing dose (48% and 32%, 10 and 20 mg/kg AZD-7762, respectively). In the mouse xenograft study in combination with Irinotecan, SW620 established tumors are treated with vehicle, Irinotecan alone, AZD-7762 alone, or AZD-7762 in combination with Irinotecan. AZD-7762 dosed alone shows insignificant antitumor activity, whereas Irinotecan alone displays striking and significant activity (%T/C with increasing dose is 9 and 1, respectively ). In combination with AZD-7762, %T/C increases significantly to -66% and -67%, respectively^[1]. AZD7762 combination with CX-5461 induces cancer cell death of Tp53-null (Tp53^-/-) Eμ-Myc lymphoma cells in vitro and in vivo^[2].