Background:

AZ20 is a potent and selective inhibitor of ATR. AZ20 inhibits ATR immunoprecipitated from HeLa nuclear extracts with an IC50 value of 5 nM and ATR mediated phosphorylation of Chk1 in HT29 colorectal adenocarcinoma tumor cells with an IC50 value of 50 nM.
ATR is an attractive new anticancer drug target whose inhibitors have potential as chemo- or radiation sensitizers or as monotherapy in tumors addicted to particular DNA-repair pathways.
AZ20 is the first reported inhibitor of ATR protein kinase demonstrating tumor growth inhibition in vivo and is therefore a useful probe molecule to aid further investigation of ATR tumor biology. AZ20 potently inhibited the growth of LoVo colorectal adenocarcinoma tumor cells in vitro. In the mTOR (pAKT) cell assay, AZ20 weak inhibited recombinant mTOR enzyme activity. AZ20 shows good selectivity against all of the PI3K isoforms together with ATM and DNA-PK, and when tested in a large panel of kinases, AZ20 shows very high general kinase selectivity.
Female nude mice bearing LoVo tumors were treated with AZ20 orally at a dose of 25 mg/kg twice daily or 50 mg/kg once daily for 13 days. AZ20 showed monotherapy in vivo antitumor efficacy in LoVo colorectal xenografts in nude mice.
参考文献:
[1]. Foote KM, Blades K, Cronin A et al. Discovery of 4-{4-[(3R)-3-Methylmorpholin-4-yl]-6- [1-(methylsulfonyl)cyclopropyl]pyrimidin-2-yl}-1H-indole (AZ20): a potent and selective inhibitor of ATR protein kinase with monotherapy in vivo antitumor activity. J Med Chem. 2013 Mar 14;56(5):2125-38.