The identification of novel p38α isoform selective kinase inhibitors having an unprecedented p38α binding mode.
| Autor: | Wrobleski ST; Department of Immunology Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543-4000, USA. stephen.wrobleski@bms.com, Lin S, Dhar TG, Dyckman AJ, Li T, Pitt S, Zhang R, Fan Y, Doweyko AM, Tokarski JS, Kish KF, Kiefer SE, Sack JS, Newitt JA, Witmer MR, McKinnon M, Barrish JC, Dodd JH, Schieven GL, Leftheris K |
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| Jazyk: | angličtina |
| Zdroj: | Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2013 Jul 15; Vol. 23 (14), pp. 4120-6. Date of Electronic Publication: 2013 May 23. |
| DOI: | 10.1016/j.bmcl.2013.05.047 |
| Abstrakt: | A novel series of p38 MAP kinase inhibitors with high selectivity for the p38α isoform over the other family members including the highly homologous p38β isoform has been identified. X-ray co-crystallographic studies have revealed an unprecedented kinase binding mode in p38α for representative analogs, 5c and 9d, in which a Leu108/Met109 peptide flip occurs within the p38α hinge region. Based on these findings, a general strategy for the rational design of additional promising p38α isoform selective inhibitors by targeting this novel binding mode is proposed. (Copyright © 2013 Elsevier Ltd. All rights reserved.) |
| Databáze: | MEDLINE |
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