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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
17
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pubmed:dateCreated |
2010-9-2
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pubmed:abstractText |
The discovery of aurora kinases as essential regulators of cell division has led to intense interest in identifying small molecule aurora kinase inhibitors for the potential treatment of cancer. A high-throughput screening effort identified pyridinyl-pyrimidine 6a as a moderately potent dual inhibitor of aurora kinases -A and -B. Optimization of this hit resulted in an anthranilamide lead (6j) that possessed improved enzyme and cellular activity and exhibited a high level of kinase selectivity. However, this anthranilamide and subsequent analogues suffered from a lack of oral bioavailability. Converting the internally hydrogen-bonded six-membered pseudo-ring of the anthranilamide to a phthalazine (8a-b) led to a dramatic improvement in oral bioavailability (38-61%F) while maintaining the potency and selectivity characteristics of the anthranilamide series. In a COLO 205 tumor pharmacodynamic assay measuring phosphorylation of the aurora-B substrate histone H3 at serine 10 (p-histone H3), oral administration of 8b at 50 mg/kg demonstrated significant reduction in tumor p-histone H3 for at least 6 h.
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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 |
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pubmed:status |
MEDLINE
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pubmed:month |
Sep
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pubmed:issn |
1520-4804
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pubmed:author |
pubmed-author:BakAnnetteA,
pubmed-author:BeXuhaiX,
pubmed-author:BellonSteveS,
pubmed-author:BushTammy LTL,
pubmed-author:CeeVictor JVJ,
pubmed-author:ChengAlan CAC,
pubmed-author:ChungGraceG,
pubmed-author:CoatsSteveS,
pubmed-author:DeakHolly LHL,
pubmed-author:EdenPatrick MPM,
pubmed-author:GallantPaul LPL,
pubmed-author:Geuns-MeyerStephanie DSD,
pubmed-author:GuYanY,
pubmed-author:HanestadKellyK,
pubmed-author:HodousBrian LBL,
pubmed-author:HuangXinX,
pubmed-author:KendallRichard LRL,
pubmed-author:LinMin-Hwa JasmineMH,
pubmed-author:MorrisonMichael JMJ,
pubmed-author:NguyenHanh NHN,
pubmed-author:OlivieriPhilip RPR,
pubmed-author:PatelVinod FVF,
pubmed-author:PaytonMarcM,
pubmed-author:RadinskyRobertR,
pubmed-author:RomeroKarinaK,
pubmed-author:RosePaul EPE,
pubmed-author:RossSandraS,
pubmed-author:SchenkelLaurie BLB,
pubmed-author:SunJi-RongJR,
pubmed-author:TangJinJ,
pubmed-author:ZhaoHuilinH
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pubmed:issnType |
Electronic
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pubmed:day |
9
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pubmed:volume |
53
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
6368-77
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pubmed:dateRevised |
2011-7-11
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pubmed:meshHeading |
pubmed-meshheading:20684549-Administration, Oral,
pubmed-meshheading:20684549-Animals,
pubmed-meshheading:20684549-Antineoplastic Agents,
pubmed-meshheading:20684549-Biological Availability,
pubmed-meshheading:20684549-Blood Proteins,
pubmed-meshheading:20684549-Cell Line, Tumor,
pubmed-meshheading:20684549-Drug Screening Assays, Antitumor,
pubmed-meshheading:20684549-Female,
pubmed-meshheading:20684549-Histones,
pubmed-meshheading:20684549-Humans,
pubmed-meshheading:20684549-Male,
pubmed-meshheading:20684549-Mice,
pubmed-meshheading:20684549-Mice, Nude,
pubmed-meshheading:20684549-Microsomes, Liver,
pubmed-meshheading:20684549-Models, Molecular,
pubmed-meshheading:20684549-Neoplasm Transplantation,
pubmed-meshheading:20684549-Phthalazines,
pubmed-meshheading:20684549-Protein Binding,
pubmed-meshheading:20684549-Protein-Serine-Threonine Kinases,
pubmed-meshheading:20684549-Pyridines,
pubmed-meshheading:20684549-Pyrimidines,
pubmed-meshheading:20684549-Rats,
pubmed-meshheading:20684549-Rats, Sprague-Dawley,
pubmed-meshheading:20684549-Structure-Activity Relationship,
pubmed-meshheading:20684549-Transplantation, Heterologous
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pubmed:year |
2010
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pubmed:articleTitle |
Discovery of a potent, selective, and orally bioavailable pyridinyl-pyrimidine phthalazine aurora kinase inhibitor.
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pubmed:affiliation |
Department of Medicinal Chemistry, Amgen Inc., 360 Binney Street, Cambridge, Massachusetts 02142 and Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, USA. vcee@amgen.com
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pubmed:publicationType |
Journal Article,
In Vitro
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