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

Bioorganic and Medicinal Chemistry Letters

Volumn 17, Issue 6, 2007, Pages 1679-1683

  Cheney, I Wayne ^a   Yan, Shunqi ^a   Appleby, Todd ^a   Walker, Heli ^a   Vo, Todd ^a   Yao, Nanhua ^a   Hamatake, Robert ^a   Hong, Zhi ^a   Wu, Jim Z ^a  

^a Valeant Research and Development   (United States)

Author keywords

Fused ring pyridone; Pim; Pim 1; Pim 1 kinase; Pim 1 kinase inhibitors; Pyridone; X ray complex structure

Indexed keywords

PROTEIN KINASE PIM 1; PROTEIN KINASE PIM 1 INHIBITOR; PYRIDONE DERIVATIVE; UNCLASSIFIED DRUG;

ARTICLE; CATALYSIS; CRYSTAL STRUCTURE; DRUG STRUCTURE; HYDROGEN BOND; IC 50; STRUCTURE ACTIVITY RELATION;

ADENOSINE TRIPHOSPHATE; CLONING, MOLECULAR; CRYSTALLOGRAPHY, X-RAY; ENZYME INHIBITORS; HUMANS; HYDROGEN BONDING; INDICATORS AND REAGENTS; MODELS, MOLECULAR; MOLECULAR CONFORMATION; MOLECULAR SEQUENCE DATA; PROTO-ONCOGENE PROTEINS C-PIM-1; PYRIDONES; RECOMBINANT PROTEINS; REVERSE TRANSCRIPTASE POLYMERASE CHAIN REACTION; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 33847058740     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2006.12.086     Document Type: Article

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26. 2, 5 mM DTT, 4% DMSO, 15 μM ATP, 1 μg GST-Pim-1, 5 μg calf thymus histones plus the test compound in a 20 μl total volume. Reactions were performed in a 384-well plate for 1 h at room temperature and were terminated by the addition of the Kinase-Glo reagent then counted on the LJL Analyst plate reader. The Z′ for the assay was 0.8.
27. 50 values were determined.
28. Protein purification: Full-length Pim-1 (residues 1-313) was PCR cloned into the bacterial expression vector pET28a in-frame with the N-terminal hexahistidine tag. Expression was carried out in BL21 (DE3) pLysS Escherichia coli in LB medium after induction with IPTG for 4 h at 28 °C. Following cell lysis, the His-tagged Pim-1 was subjected to a sequential purification scheme initially incorporating FPLC using a nickel-chelating Sepharose column followed by a Resource Q ion exchange column and lastly a Superdex 75 gel filtration column. Using this process we recovered milligram quantities of Pim-1 with purity sufficient for attempting crystallization.
29. The Pim-1/inhibitor complex was obtained by combining 25 μl protein (12 mg/ml) with 0.35 μl of 20 mM compound 1 in DMSO. The samples were incubated at 4 °C for 1-2 h. Co-crystals were grown using a sitting-drop vapor diffusion tray with a crystallization solution containing 1.0 M ammonium phosphate (dibasic), 300 mM sodium chloride, and 100 mM citrate buffer (pH 5.0). Crystallization plates were incubated at 23 °C and optimal crystal size was reached in approximately 10 days. Data acquisition was performed on a Rigaku R-Axis IV+ detector mounted on a Rigaku RUH3R generator operating at 50 kV and 100 mA. Measurement intensities were integrated, scaled, and merged using HKL software (Z. Otwinoski and W. Minor).
30. Coordinates for the complex structure of Pim-1/compound 1 have been deposited with the Protein Data Bank (www.rcsb.org) under PDB code 2OBJ.