Identification and structure–activity relationships of substituted pyridones as inhibitors of Pim-1 kinase

• Published in: Bioorganic & medicinal chemistry letters 2007-03, Vol.17 (6), p.1679-1683
• Main Authors: Cheney, I. Wayne, Yan, Shunqi, Appleby, Todd, Walker, Heli, Vo, Todd, Yao, Nanhua, Hamatake, Robert, Hong, Zhi, Wu, Jim Z.
• Format: Article
• Language: English
• Subjects: Adenosine Triphosphate - metabolism; Biological and medical sciences; Cloning, Molecular; Crystallography, X-Ray; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - pharmacology; Fused-ring pyridone; Humans; Hydrogen Bonding; Indicators and Reagents; Medical sciences; Miscellaneous; Models, Molecular; Molecular Conformation; Molecular Sequence Data; Pharmacology. Drug treatments; Pim; Pim-1; Pim-1 kinase; Pim-1 kinase inhibitors; Proto-Oncogene Proteins c-pim-1 - antagonists & inhibitors; Proto-Oncogene Proteins c-pim-1 - chemical synthesis; Proto-Oncogene Proteins c-pim-1 - genetics; Pyridone; Pyridones - chemical synthesis; Pyridones - pharmacology; Recombinant Proteins - chemistry; Reverse Transcriptase Polymerase Chain Reaction; Structure-Activity Relationship; X-ray complex structure
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2006.12.086

A novel class of pyridone-based inhibitors of Pim-1 kinase is reported. A complex crystal structure of Pim-1/compound 1 (IC 50 of 1 = 50 nM) defined an inhibitory mechanism of action. 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.