| Biological characterization of 2-aminothiazole-derived Cdk4/6 selective inhibitor in vitro and in vivo. | |
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MedLine Citation:
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PMID: 20372067 Owner: NLM Status: In-Data-Review |
Abstract/OtherAbstract:
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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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Authors:
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Hiroshi Hirai; Toshiyasu Shimomura; Makiko Kobayashi; Tomohiro Eguchi; Eri Taniguchi; Kazuhiro Fukasawa; Takumitsu Machida; Hiroko Oki; Tsuyoshi Arai; Koji Ichikawa; Shinichi Hasako; Kyosuke Haze; Tsutomu Kodera; Nobuhiko Kawanishi; Ikuko Takahashi-Suziki; Yoko Nakatsuru; Hidehito Kotani; Yoshikazu Iwasawa |
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Publication Detail:
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Type: Journal Article Date: 2010-04-15 |
Journal Detail:
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Title: Cell cycle (Georgetown, Tex.) Volume: 9 ISSN: 1551-4005 ISO Abbreviation: Cell Cycle Publication Date: 2010 Apr |
Date Detail:
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Created Date: 2011-05-17 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 101137841 Medline TA: Cell Cycle Country: United States |
Other Details:
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Languages: eng Pagination: 1590-600 Citation Subset: IM |
Affiliation:
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Merck Research Laboratories, Tsukuba, Ibaraki, Japan. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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