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

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• 作者：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 ; Paula Perkins ; Abid Suleman ; Kin Tam ; Pia Thommes ; Rebecca Broadhurst ; Christine Wood
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：March 14, 2013
• 年：2013
• 卷：56
• 期：5
• 页码：2125-2138
• 全文大小：625K
• 年卷期：v.56,no.5(March 14, 2013)
• ISSN：1520-4804

文摘

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.