title: The identification of novel p38α isoform selective kinase inhibitors having an unprecedented p38α binding mode.
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.
authors.affiliation: Department of Immunology Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543-4000, USA. stephen.wrobleski@bms.com
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Wrobleski
authors.forename: Shuqun
authors.initials: S
authors.lastname: Lin
authors.forename: T G Murali
authors.initials: TG
authors.lastname: Dhar
authors.forename: Alaric J
authors.initials: AJ
authors.lastname: Dyckman
authors.forename: Tianle
authors.initials: T
authors.lastname: Li
authors.forename: Sidney
authors.initials: S
authors.lastname: Pitt
authors.forename: Rosemary
authors.initials: R
authors.lastname: Zhang
authors.forename: Yi
authors.initials: Y
authors.lastname: Fan
authors.forename: Arthur M
authors.initials: AM
authors.lastname: Doweyko
authors.forename: John S
authors.initials: JS
authors.lastname: Tokarski
authors.forename: Kevin F
authors.initials: KF
authors.lastname: Kish
authors.forename: Susan E
authors.initials: SE
authors.lastname: Kiefer
authors.forename: John S
authors.initials: JS
authors.lastname: Sack
authors.forename: John A
authors.initials: JA
authors.lastname: Newitt
authors.forename: Mark R
authors.initials: MR
authors.lastname: Witmer
authors.forename: Murray
authors.initials: M
authors.lastname: McKinnon
authors.forename: Joel C
authors.initials: JC
authors.lastname: Barrish
authors.forename: John H
authors.initials: JH
authors.lastname: Dodd
authors.forename: Gary L
authors.initials: GL
authors.lastname: Schieven
authors.forename: Katerina
authors.initials: K
authors.lastname: Leftheris
mesh_terms: D001665:Binding Sites; D018360:Crystallography, X-Ray; D006801:Humans; D006860:Hydrogen Bonding; D048308:Mitogen-Activated Protein Kinase 14 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship
chemical_list: D020033:Protein Isoforms; D047428:Protein Kinase Inhibitors; D048308:Mitogen-Activated Protein Kinase 14