Document Detail

Biological characterization of 2-aminothiazole-derived Cdk4/6 selective inhibitor in vitro and in vivo.
MedLine Citation:
PMID:  20372067     Owner:  NLM     Status:  In-Data-Review    
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.
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:
Type:  Journal Article     Date:  2010-04-15
Journal Detail:
Title:  Cell cycle (Georgetown, Tex.)     Volume:  9     ISSN:  1551-4005     ISO Abbreviation:  Cell Cycle     Publication Date:  2010 Apr 
Date Detail:
Created Date:  2011-05-17     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101137841     Medline TA:  Cell Cycle     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1590-600     Citation Subset:  IM    
Merck Research Laboratories, Tsukuba, Ibaraki, Japan.
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