Isoindolinone Inhibitors of the Murine Double Minute 2 (MDM2)-p53 Protein鈭扨rotein Interaction: Structure鈭扐ctivity Studies Leading to Improved Potency

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• 作者：Ian R. Hardcastle ; Junfeng Liu ; Eric Valeur ; Anna Watson ; Shafiq U. Ahmed ; Timothy J. Blackburn ; Karim Bennaceur ; William Clegg ; Catherine Drummond ; Jane A. Endicott ; Bernard T. Golding ; Roger J. Griffin ; Jan Gruber ; Karen Haggerty ; Ross W. Harrington ; Claire Hutton ; Stuart Kemp ; Xiaohong Lu ; James M. McDonnell ; David R. Newell ; Martin E. M. Noble ; Sara L. Payne ; Charlotte H. Revill ; Christiane Riedinger ; Qing Xu ; John Lunec
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：March 10, 2011
• 年：2011
• 卷：54
• 期：5
• 页码：1233-1243
• 全文大小：1212K
• 年卷期：v.54,no.5(March 10, 2011)
• ISSN：1520-4804

文摘

Inhibition of the MDM2-p53 interaction has been shown to produce an antitumor effect, especially in MDM2 amplified tumors. The isoindolinone scaffold has proved to be versatile for the discovery of MDM2-p53 antagonists. Optimization of previously reported inhibitors, for example, NU8231 (7) and NU8165 (49), was guided by MDM2 NMR titrations, which indicated key areas of the binding interaction to be explored. Variation of the 2-N-benzyl and 3-alkoxy substituents resulted in the identification of 3-(4-chlorophenyl)-3-((1-(hydroxymethyl)cyclopropyl)methoxy)-2-(4-nitrobenzyl)isoindolin-1-one (74) as a potent MDM2-p53 inhibitor (IC₅₀ = 0.23 卤 0.01 渭M). Resolution of the enantiomers of 74 showed that potent MDM2-p53 activity primarily resided with the (+)-R-enantiomer (74a; IC₅₀ = 0.17 卤 0.02 渭M). The cellular activity of key compounds has been examined in cell lines with defined p53 and MDM2 status. Compound 74a activates p53, MDM2, and p21 transcription in MDM2 amplified cells and shows moderate selectivity for wild-type p53 cell lines in growth inhibition assays.