The identification of novel p38I- isoform selective kinase inhibitors having an unprecedented p38I- binding mode

• Published in: Bioorganic & medicinal chemistry letters Vol. 23; no. 14; pp. 4120 - 4126
• Main Authors: Wrobleski, Stephen, Lin, Shuqun, Dhar, T G, Dyckman, Alaric, Li, Tianle, Pitt, Sidney, Zhang, Rosemary, Fan, Yi, Doweyko, Arthur, Tokarski, John, Kish, Kevin, Kiefer, Susan, Sack, John, Newitt, John, Witmer, Mark, McKinnon, Murray, Barrish, Joel, Dodd, John, Schieven, Gary, Leftheris, Katerina
• Format: Journal Article
• Language: English
• Published: 01-07-2013
• Subjects: Ionizing radiation
• ISSN: 0960-894X
• DOI: 10.1016/j.bmcl.2013.05.047

A novel series of p38 MAP kinase inhibitors with high selectivity for the p38I- isoform over the other family members including the highly homologous p38I2 isoform has been identified. X-ray co-crystallographic studies have revealed an unprecedented kinase binding mode in p38I- for representative analogs, 5c and 9d, in which a Leu108/Met109 peptide flip occurs within the p38I- hinge region. Based on these findings, a general strategy for the rational design of additional promising p38I- isoform selective inhibitors by targeting this novel binding mode is proposed.