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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
9
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pubmed:dateCreated |
2007-4-26
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pubmed:abstractText |
The Aurora kinases have been the subject of considerable interest as targets for the development of new anticancer agents. While evidence suggests inhibition of Aurora B kinase gives rise to the more pronounced antiproliferative phenotype, the most clinically advanced agents reported to date typically inhibit both Aurora A and B. We have discovered a series of pyrazoloquinazolines, some of which show greater than 1000-fold selectivity for Aurora B over Aurora A kinase activity, in recombinant enzyme assays. These compounds have been designed for parenteral administration and achieve high levels of solubility by virtue of their ability to be delivered as readily activated phosphate derivatives. The prodrugs are comprehensively converted to the des-phosphate form in vivo, and the active species have advantageous pharmacokinetic properties and safety pharmacology profiles. The compounds display striking in vivo activity, and compound 5 (AZD1152) has been selected for clinical evaluation and is currently in phase 1 clinical trials.
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Antineoplastic Agents,
http://linkedlifedata.com/resource/pubmed/chemical/Cytochrome P-450 Enzyme System,
http://linkedlifedata.com/resource/pubmed/chemical/ERG1 potassium channel,
http://linkedlifedata.com/resource/pubmed/chemical/Ether-A-Go-Go Potassium Channels,
http://linkedlifedata.com/resource/pubmed/chemical/Histones,
http://linkedlifedata.com/resource/pubmed/chemical/Phosphoric Acid Esters,
http://linkedlifedata.com/resource/pubmed/chemical/Prodrugs,
http://linkedlifedata.com/resource/pubmed/chemical/Protein-Serine-Threonine Kinases,
http://linkedlifedata.com/resource/pubmed/chemical/Pyrazoles,
http://linkedlifedata.com/resource/pubmed/chemical/Quinazolines,
http://linkedlifedata.com/resource/pubmed/chemical/Recombinant Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/aurora kinase
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pubmed:status |
MEDLINE
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pubmed:month |
May
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pubmed:issn |
0022-2623
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pubmed:author |
pubmed-author:BradyMadeleine CMC,
pubmed-author:BrightwellStephenS,
pubmed-author:BrownElaineE,
pubmed-author:CrafterClaireC,
pubmed-author:De SaviChrisC,
pubmed-author:DoussonCyril BCB,
pubmed-author:FooteKevin MKM,
pubmed-author:GreenStephenS,
pubmed-author:HatterGlennG,
pubmed-author:HeatonSimon PSP,
pubmed-author:HeronNicola MNM,
pubmed-author:HillGeorge BGB,
pubmed-author:JohnsonTrevorT,
pubmed-author:JungFrédéric HFH,
pubmed-author:KearneySarahS,
pubmed-author:KeenNicholas JNJ,
pubmed-author:KhatriLizL,
pubmed-author:LohmannJean-Jacques MJJ,
pubmed-author:McKillopDavidD,
pubmed-author:MortlockAndrew AAA,
pubmed-author:OdedraRajeshR,
pubmed-author:PasquetGeorgesG,
pubmed-author:PerkinsDavidD,
pubmed-author:RenaudFabriceF,
pubmed-author:RheadSteveS,
pubmed-author:RobertsNicola JNJ,
pubmed-author:SIGELI MIM,
pubmed-author:ThompsonKatherineK,
pubmed-author:WarinNicolasN,
pubmed-author:WedgeStephen RSR,
pubmed-author:WilkinsonRobert WRW
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pubmed:issnType |
Print
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pubmed:day |
3
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pubmed:volume |
50
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
2213-24
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pubmed:dateRevised |
2011-7-11
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pubmed:meshHeading |
pubmed-meshheading:17373783-Animals,
pubmed-meshheading:17373783-Antineoplastic Agents,
pubmed-meshheading:17373783-Cell Division,
pubmed-meshheading:17373783-Cell Line, Tumor,
pubmed-meshheading:17373783-Cytochrome P-450 Enzyme System,
pubmed-meshheading:17373783-Drug Screening Assays, Antitumor,
pubmed-meshheading:17373783-Ether-A-Go-Go Potassium Channels,
pubmed-meshheading:17373783-Female,
pubmed-meshheading:17373783-Histones,
pubmed-meshheading:17373783-Humans,
pubmed-meshheading:17373783-Male,
pubmed-meshheading:17373783-Mice,
pubmed-meshheading:17373783-Mice, Nude,
pubmed-meshheading:17373783-Phosphoric Acid Esters,
pubmed-meshheading:17373783-Phosphorylation,
pubmed-meshheading:17373783-Prodrugs,
pubmed-meshheading:17373783-Protein Binding,
pubmed-meshheading:17373783-Protein-Serine-Threonine Kinases,
pubmed-meshheading:17373783-Pyrazoles,
pubmed-meshheading:17373783-Quinazolines,
pubmed-meshheading:17373783-Rats,
pubmed-meshheading:17373783-Recombinant Proteins,
pubmed-meshheading:17373783-Structure-Activity Relationship,
pubmed-meshheading:17373783-Transplantation, Heterologous
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pubmed:year |
2007
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pubmed:articleTitle |
Discovery, synthesis, and in vivo activity of a new class of pyrazoloquinazolines as selective inhibitors of aurora B kinase.
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pubmed:affiliation |
AstraZeneca Pharmaceuticals, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
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pubmed:publicationType |
Journal Article
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