The identification of novel p38¦Á isoform selective kinase inhibitors having an unprecedented p38¦Á binding mode
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- 作者：Stephen T. Wrobleski ; Shuqun Lin ; T.G. Murali Dhar ; Alaric J. Dyckman ; Tianle Li ; Sidney Pitt ; Rosemary Zhang ; Yi Fan ; Arthur M. Doweyko ; John S. Tokarski ; Kevin F. Kish ; Susan E. Kiefer ; John S. Sack ; John A. Newitt ; Mark R. Witmer ; Murray McKinnon ; Joel C. Barrish ; John H. Dodd ; Gary L. Schieven ; Katerina Leftheris ; et al.
- 关键词：p38 ; Kinase ; Inhibitors
- 刊名：Bioorganic and Medicinal Chemistry Letters
- 出版年：2013
- 出版时间：15 July, 2013
- 年：2013
- 卷：23
- 期：14
- 页码：4120-4126
- 全文大小：2108 K
文摘
A novel series of p38 MAP kinase inhibitors with high selectivity for the p38¦Á isoform over the other family members including the highly homologous p38¦Â isoform has been identified. X-ray co-crystallographic studies have revealed an unprecedented kinase binding mode in p38¦Á for representative analogs, 5c and 9d, in which a Leu108/Met109 peptide flip occurs within the p38¦Á hinge region. Based on these findings, a general strategy for the rational design of additional promising p38¦Á isoform selective inhibitors by targeting this novel binding mode is proposed.