Mechanism of action: checkpoint kinase 1 and 2 (Chk1/2) inhibitor

Preclinical pharmacology

AZD7762 is a potent inhibitor of Chk1 that binds in the ATP binding pocket (IC50 of 5nM; Ki of 3.6nM). AZD7762 has activity on a range of other kinases {examples with a < 5‑fold selectivity included Rous sarcoma oncogene cellular homolog (SRC) family members (e.g., Fgr, Fyn, lymphocyte-specific protein-tyrosine kinase [Lck], and Lyn, but not SRC), Flt1/3, colony stimulating factor receptor (CSF1R), RET, Abelson tyrosine kinase (Abl), and checkpoint kinase 2 (Chk2)}. It is not known if these in vitro kinase inhibitions translate into an effect in vivo.

In combination with DNA-damaging agents (gemcitabine, topotecan, doxorubicin, and cisplatin), AZD7762 inhibits tumour cell growth in vitro with a mode of action that correlates with Chk1 inhibition and abrogation of the Gap 2 (G2) and S phase checkpoints. Rightward shifts in 50% growth inhibition (GI50) values over DNA-damaging agents alone ranged from 5- to 20-fold with gemcitabine demonstrating the largest shifts followed by topotecan. In combination with radiation, AZD7762 enhances tumour cell growth inhibition and death with survival enhancement ratios ranging from 1.7 to 1.9. Triple combinations with AZD7762, gemcitabine, and radiation yield the largest survival enhancement ratios.

In vivo studies established that exposure time proportionally correlates with PD activity, and that plasma exposure for a least 8 hours above EC50 was required for maximum PD activity. In the rat PD model, the doses giving ED50 and ED100 were 15mg/m2 (2.5mg/kg) and 30mg/m2 (5mg/kg), respectively.

Additional Information

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Gene information from the NCBi

This compound works on the following genes: