1. The identification of novel p38α isoform selective kinase inhibitors having an unprecedented p38α binding mode.
- Author
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Wrobleski ST, 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, and Leftheris K
- Subjects
- Binding Sites, Crystallography, X-Ray, Humans, Hydrogen Bonding, Mitogen-Activated Protein Kinase 14 metabolism, Molecular Dynamics Simulation, Protein Binding, Protein Isoforms antagonists & inhibitors, Protein Isoforms metabolism, Protein Kinase Inhibitors chemical synthesis, Protein Kinase Inhibitors metabolism, Protein Structure, Tertiary, Structure-Activity Relationship, Mitogen-Activated Protein Kinase 14 antagonists & inhibitors, Protein Kinase Inhibitors chemistry
- Abstract
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.)
- Published
- 2013
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