title: Identification and structure-activity relationships of substituted pyridones as inhibitors of Pim-1 kinase.
abstract: A novel series of highly potent substituted pyridone Pim-1 kinase inhibitors is described. Structural requirements for in vitro activity are outlined as well as a complex crystal structure with the most potent Pim-1 inhibitor reported (IC(50)=50 nM). A hydrogen bond matrix involving the Pim-1 inhibitor, two water molecules, and the catalytic core, together with a potential weak hydrogen bond between an aromatic hydrogen on the R(1) phenyl ring and a main-chain carbonyl of Pim-1, accounts for the overall potency of this inhibitor.
authors.affiliation: Valeant Pharmaceuticals Research and Development, 3300 Hyland Avenue, Costa Mesa, CA 92626, USA. wcheney@ardeabiosciences.com
authors.forename: I Wayne
authors.initials: IW
authors.lastname: Cheney
authors.forename: Shunqi
authors.initials: S
authors.lastname: Yan
authors.forename: Todd
authors.initials: T
authors.lastname: Appleby
authors.forename: Heli
authors.initials: H
authors.lastname: Walker
authors.forename: Todd
authors.initials: T
authors.lastname: Vo
authors.forename: Nanhua
authors.initials: N
authors.lastname: Yao
authors.forename: Robert
authors.initials: R
authors.lastname: Hamatake
authors.forename: Zhi
authors.initials: Z
authors.lastname: Hong
authors.forename: Jim Z
authors.initials: JZ
authors.lastname: Wu
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D003001:Cloning, Molecular; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D006801:Humans; D006860:Hydrogen Bonding; D007202:Indicators and Reagents; D008958:Models, Molecular; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D051573:Proto-Oncogene Proteins c-pim-1 / Q000037:antagonists & inhibitors* / Q000138:chemical synthesis / Q000235:genetics; D011728:Pyridones / Q000138:chemical synthesis* / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000737:chemistry; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D007202:Indicators and Reagents; D011728:Pyridones; D011994:Recombinant Proteins; D000255:Adenosine Triphosphate; D051573:Proto-Oncogene Proteins c-pim-1