Novel ATP competitive MK2 inhibitors with potent biochemical and cell-based activity throughout the series

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• 作者：Arthur Oubrie ; Allard Kaptein ; Edwin de Zwart ; Niels Hoogenboom ; Rianne Goorden ; Bas van de Kar ; Maaike van Hoek ; Vera de Kimpe ; Ruud van der Heijden ; Judith Borsboom ; Bert Kazemier ; Jeroen de Roos ; Michiel Scheffers ; Jos Lommerse ; Carsten Schultz-Fademrecht ; Tjeerd Barf ; ^{tjeerd.barf@covalution.com}
• 关键词：MAPKAPK2 ; MK2 ; Anti-TNF¦Á ; HSP27 ; Rheumatoid arthritis
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2012
• 出版时间：1 January, 2012
• 年：2012
• 卷：22
• 期：1
• 页码：613-618
• 全文大小：576 K

文摘

Optimization of our previously described pyrrolopiperidone series led to the identification of a new benzamide sub-series, which exhibits consistently high potency in biochemical and cell-based assays throughout the series. Strong inhibition of LPS-induced production of the cytokine TNF¦Á is coupled to the regulation of HSP27 phosphorylation, indicating that the observed cellular effects result from the inhibition of MK2. X-ray crystallographic and computational analyses provide a rationale for the high potency of the series.