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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
8
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pubmed:dateCreated |
2011-5-17
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pubmed:abstractText |
Abnormalities in the p16INK4a/ cyclin-dependent kinase (Cdk)4, 6/ Retinoblastoma (Rb) pathway frequently occur in various human cancers. Thus, Cdk4/6 is an attractive target for cancer therapy. Here we report the biological characterization of a 2-aminothiazole-derived Cdk4/6 selective inhibitor, named Compound A in vitro and in vivo. Compound A potently inhibits Cdk4 and Cdk6 with high selectivity (more than 57-fold) against other Cdks and 45 serine/threonine and tyrosine kinases. Compound A inhibits Rb protein (pRb) phosphorylation at Ser780, inhibits E2F-dependent transcription, and induces cell-cycle arrest at G1 in the T98G human glioma cell line. Among 82 human cells derived from various tissues, cell lines derived from hematological cancers (leukemia/lymphoma) tended to be more sensitive to Compound A in cell proliferation assay. Rb-negative cells tended to be insensitive to Compound A, as we had expected. In a nude rat xenograft model, Compound A inhibited pRb phosphorylation and bromodeoxyuridine (BrdU) incorporation in Eol-1 xenograft tumor at plasma concentration of 510 nM. Interestingly Compound A only moderately inhibited those pharmacodynamic and cell cycle parameters of normal crypt cells in small intestine even at 5 times higher plasma concentration. In F344 rats, Compound A did not cause immunosuppression even at 17 times higher plasma conc. These results suggest that Cdk4/6 selective inhibitors only moderately affects on the cell cycle of normal proliferating tissues and has a safer profile than pan-Cdk inhibitor in vivo.
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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/2-aminothiazole,
http://linkedlifedata.com/resource/pubmed/chemical/Cyclin-Dependent Kinase 2,
http://linkedlifedata.com/resource/pubmed/chemical/Cyclin-Dependent Kinase 4,
http://linkedlifedata.com/resource/pubmed/chemical/Cyclin-Dependent Kinase 6,
http://linkedlifedata.com/resource/pubmed/chemical/E2F Transcription Factors,
http://linkedlifedata.com/resource/pubmed/chemical/Protein Kinase Inhibitors,
http://linkedlifedata.com/resource/pubmed/chemical/Pyrimidines,
http://linkedlifedata.com/resource/pubmed/chemical/RNA, Small Interfering,
http://linkedlifedata.com/resource/pubmed/chemical/Retinoblastoma Protein,
http://linkedlifedata.com/resource/pubmed/chemical/Thiazoles
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pubmed:status |
MEDLINE
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pubmed:month |
Apr
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pubmed:issn |
1551-4005
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pubmed:author |
pubmed-author:AraiTsuyoshiT,
pubmed-author:EguchiTomohiroT,
pubmed-author:FukasawaKazuhiroK,
pubmed-author:HasakoShinichiS,
pubmed-author:HazeKyosukeK,
pubmed-author:HiraiHiroshiH,
pubmed-author:IchikawaKojiK,
pubmed-author:IwasawaYoshikazuY,
pubmed-author:KawanishiNobuhikoN,
pubmed-author:KobayashiMakikoM,
pubmed-author:KoderaTsutomuT,
pubmed-author:KotaniHidehitoH,
pubmed-author:MachidaTakumitsuT,
pubmed-author:NakatsuruYokoY,
pubmed-author:OkiHirokoH,
pubmed-author:ShimomuraToshiyasuT,
pubmed-author:Takahashi-SuzikiIkukoI,
pubmed-author:TaniguchiEriE
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pubmed:issnType |
Electronic
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pubmed:day |
15
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pubmed:volume |
9
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
1590-600
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pubmed:meshHeading |
pubmed-meshheading:20372067-Animals,
pubmed-meshheading:20372067-Cell Line, Tumor,
pubmed-meshheading:20372067-Cyclin-Dependent Kinase 2,
pubmed-meshheading:20372067-Cyclin-Dependent Kinase 4,
pubmed-meshheading:20372067-Cyclin-Dependent Kinase 6,
pubmed-meshheading:20372067-E2F Transcription Factors,
pubmed-meshheading:20372067-G1 Phase,
pubmed-meshheading:20372067-Humans,
pubmed-meshheading:20372067-Male,
pubmed-meshheading:20372067-Phosphorylation,
pubmed-meshheading:20372067-Protein Kinase Inhibitors,
pubmed-meshheading:20372067-Pyrimidines,
pubmed-meshheading:20372067-RNA, Small Interfering,
pubmed-meshheading:20372067-RNA Interference,
pubmed-meshheading:20372067-Rats,
pubmed-meshheading:20372067-Rats, Nude,
pubmed-meshheading:20372067-Retinoblastoma Protein,
pubmed-meshheading:20372067-Thiazoles,
pubmed-meshheading:20372067-Transplantation, Heterologous
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pubmed:year |
2010
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pubmed:articleTitle |
Biological characterization of 2-aminothiazole-derived Cdk4/6 selective inhibitor in vitro and in vivo.
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pubmed:affiliation |
Department of Oncology, Merck Research Laboratories, Tsukuba, Ibaraki, Japan. yrdyc661@yahoo.co.jp
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pubmed:publicationType |
Journal Article
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