AZD-7762 (hydrochloride)

AZD-7762 hydrochloride is a potent ATP-competitive checkpoint kinase (Chk) inhibitor in with an IC₅₀ of 5 nM for Chk1. IC50 & Target:IC50: 5 nM (ChK1), 5 nM (ChK2)^[1] In Vitro: AZD-7762 hydrochloride (AZD7762) is an equally potent inhibitor of Chk1 and Chk2 in vitro. AZD-7762 hydrochloride potently inhibits Chk1 and Chk2, abrogates DNA damage-induced S and G₂ checkpoints, enhances the efficacy of NSC 613327 and SKF 104864A, and modulates downstream checkpoint pathway proteins. AZD-7762 hydrochloride 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 hydrochloride is determined to be 3.6 nM. Kinetic characterization suggests that AZD-7762 hydrochloride binds in the ATP-binding site of Chk1 and is thought to compete directly for ATP binding in a reversible manner. AZD-7762 hydrochloride 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 rat H460-DNp53 xenograft studies, AZD-7762 hydrochloride (10 mg/kg and 20 mg/kg) potentiates the antitumor activity of NSC 613327 in a dose-dependent manner. That is, the inhibition rate (%T/C) decreases to 48% and 32%, respectively, with increasing dose. In a mouse xenograft study in combination with CPT-11, treatment with AZD-7762 hydrochloride in combination with CPT-11 significantly increased CPT-11 activity with a significant increase in %T/C to -66% and -67%, respectively^[1]. AZD7762 hydrochloride in combination with CX-5461 induces Tp53-null (Tp53^-/-) Eμ-Myc in vitro and in vivo Lymphoma cell death^[2].