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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

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

Kevin M Foote, Kevin Blades, Anna Cronin, Shaun Fillery, Sylvie S Guichard, Lorraine Hassall, Ian Hickson, Xavier Jacq, Philip J Jewsbury, Thomas M McGuire, J Willem M Nissink, Rajesh Odedra, Ken Page, etc.

J Med Chem. 2013 Mar 14;56(5):2125-38.

PMID: 23394205

Abstract:

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. We describe the discovery and synthesis of a series of sulfonylmorpholinopyrimidines that show potent and selective ATR inhibition. Optimization from a high quality screening hit within tight SAR space led to compound 6 (AZ20) which inhibits ATR immunoprecipitated from HeLa nuclear extracts with an IC50 of 5 nM and ATR mediated phosphorylation of Chk1 in HT29 colorectal adenocarcinoma tumor cells with an IC50 of 50 nM. Compound 6 potently inhibits the growth of LoVo colorectal adenocarcinoma tumor cells in vitro and has high free exposure in mouse following moderate oral doses. At well tolerated doses 6 leads to significant growth inhibition of LoVo xenografts grown in nude mice. Compound 6 is a useful compound to explore ATR pharmacology in vivo.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP1233339224	AZ20		1233339-22-4	Price

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