ABSTRACT
Mps1 is a dual specificity protein kinase that is essential for the bipolar attachment of chromosomes to the mitotic spindle and for maintaining the spindle assembly checkpoint until all chromosomes are properly attached. Mps1 is expressed at high levels during mitosis and is abundantly expressed in cancer cells. Disruption of Mps1 function induces aneuploidy and cell death. We report the identification of MPI-0479605, a potent and selective ATP competitive inhibitor of Mps1. Cells treated with MPI-0479605 undergo aberrant mitosis, resulting in aneuploidy and formation of micronuclei. In cells with wild-type p53, this promotes the induction of a postmitotic checkpoint characterized by the ATM- and RAD3-related-dependent activation of the p53-p21 pathway. In both wild-type and p53 mutant cells lines, there is a growth arrest and inhibition of DNA synthesis. Subsequently, cells undergo mitotic catastrophe and/or an apoptotic response. In xenograft models, MPI-0479605 inhibits tumor growth, suggesting that drugs targeting Mps1 may have utility as novel cancer therapeutics.
Subject(s)
Adenine/analogs & derivatives , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Morpholines/pharmacology , Morpholines/therapeutic use , Neoplasms/drug therapy , Protein Serine-Threonine Kinases/antagonists & inhibitors , Adenine/isolation & purification , Adenine/pharmacology , Adenine/therapeutic use , Animals , Antineoplastic Agents/isolation & purification , Cell Line, Tumor , HCT116 Cells , Humans , Mice , Mice, Nude , Mitosis/drug effects , Mitosis/physiology , Models, Biological , Molecular Weight , Morpholines/isolation & purification , Neoplasms/pathology , Protein Kinase Inhibitors/isolation & purification , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Small Molecule Libraries/chemistry , Xenograft Model Antitumor AssaysABSTRACT
In an effort to monitor leakage from underground CO(2) storage, a field-deployable analyzer capable of rapidly measuring the CO(2) mixing ratio and δ(13)C values (±0.05 ppm(v) ± 0.2, 60 s) was deployed to distinguish between biogenic and fossil CO(2) sources. The analyzer was interfaced with a multiport inlet unit to allow autonomous sampling from multiple locations. The instrument and inlet interface were deployed at the Zero Emissions Research and Technology (ZERT) site (Bozeman, Montana, July 14-22, 2009) during a controlled, subsurface release of CO(2) depleted in (13)C. A biogenic diurnal cycle was observed far from the release, and the associated Keeling plot suggested a CO(2) source (δ(13)C = -27.0 ± 0.5) consistent with local C(3) vegetation. Inlets near the leak showed large CO(2) mixing ratios (388/>40 000 ppm(v)) whose predominant source was the release CO(2) (inferred δ(13)C = -58.2 ± 0.7). Measurements 3 m from the source showed diurnal CO(2) cycles (382-2400 ppm(v)) influenced by leaked CO(2), possibly due to diel air mixing. Finally, the data from all of the sampling inlets was combined to spatially localize the leak position.
ABSTRACT
A series of 4,5-disubstituted cis-pyrrolidinones was investigated as inhibitors of 17beta-HSD II for the treatment of osteoporosis. Biochemical data for several compounds are given. Compound 42 was selected as the lead candidate.
Subject(s)
17-Hydroxysteroid Dehydrogenases/antagonists & inhibitors , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Pyrrolidinones/chemistry , Pyrrolidinones/pharmacology , Thiophenes/chemistry , Thiophenes/pharmacology , 17-Hydroxysteroid Dehydrogenases/metabolism , Animals , Cell Line , Enzyme Inhibitors/chemistry , Humans , Inhibitory Concentration 50 , Macaca fascicularis , Pyrrolidinones/chemical synthesis , Rats , Stereoisomerism , Structure-Activity Relationship , Thiophenes/chemical synthesisABSTRACT
4,5-Disubstituted cis-pyrrolidinones were investigated as inhibitors of type II 17beta-hydroxysteroid dehydrogenase (17beta-HSD). Early structure-activity relationship patterns for this class of compounds are discussed.
Subject(s)
17-Hydroxysteroid Dehydrogenases/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Pyrrolidinones/pharmacology , 17-Hydroxysteroid Dehydrogenases/metabolism , Enzyme Inhibitors/chemistry , Humans , Pyrrolidinones/chemistry , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Bis-aryl ureas have been disclosed previously as a potent class of Raf kinase inhibitors. Modifications in the amide portion led to an improvement in aqueous solubility, an important characteristic for an oral drug. Based on this finding, we hypothesize that this portion of the molecule is directed towards the solvent in Raf-1.
