National Center for
2OBJ: Crystal Structure of Human Pim-1 Kinase in Complex With Inhibitor
Identification and structure-activity relationships of substituted pyridones as inhibitors of Pim-1 kinase
Bioorg. Med. Chem. Lett. (2007) 17 p.1679-1683
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.