Identification and structure-activity relationships of substituted pyridones as inhibitors of Pim-1 kinase.
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.
Cheney
I Wayne
IW
Valeant Pharmaceuticals Research and Development, 3300 Hyland Avenue, Costa Mesa, CA 92626, USA. wcheney@ardeabiosciences.com
Yan
Shunqi
S
Appleby
Todd
T
Walker
Heli
H
Vo
Todd
T
Yao
Nanhua
N
Hamatake
Robert
R
Hong
Zhi
Z
Wu
Jim Z
JZ
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
D004791:Enzyme Inhibitors; D007202:Indicators and Reagents; D011728:Pyridones; D011994:Recombinant Proteins; D000255:Adenosine Triphosphate; D051573:Proto-Oncogene Proteins c-pim-1