Potent anti-tumor activity of a macrocycle-quinoxalinone class pan-Cdk inhibitor in vitro and in vivo
| Autor: | Yoshikazu Iwasawa, Nobuhiko Kawanishi, Tsutomu Kodera, Koji Ichikawa, Toru Takaki, Yoko Nakatsuru, Tsuyoshi Arai, Makiko Kobayashi, Hiroshi Hirai, Shinichi Hasako, Kazuhiro Fukasawa, Ikuko Takahashi-Suziki, Toshiyasu Shimomura, Takumitsu Machida, Tomohiro Eguchi, Hiroko Oki, Hidehito Kotani |
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| Rok vydání: | 2009 |
| Předmět: |
Macrocyclic Compounds
Antineoplastic Agents Substrate Specificity chemistry.chemical_compound Leukocyte Count Rats Nude In vivo Cyclin-dependent kinase Quinoxalines Animals Humans Pharmacology (medical) Cell Proliferation Pharmacology biology Cell Death Dose-Response Relationship Drug Cell growth Kinase Cell Cycle Retinoblastoma protein Cell cycle HCT116 Cells Molecular biology Xenograft Model Antitumor Assays Cyclin-Dependent Kinases Rats Oncology chemistry Bromodeoxyuridine biology.protein Female Growth inhibition CDK inhibitor |
| Zdroj: | Investigational new drugs. 29(4) |
| ISSN: | 1573-0646 |
| Popis: | Deregulation of cell-cycle control is a hallmark of cancer. Thus, cyclin-dependent kinases (Cdks) are an attractive target for the development of anti-cancer drugs. Here, we report the biological characterization of a highly potent pan-Cdk inhibitor with a macrocycle-quinoxalinone structure. Compound M inhibited Cdk1, 2, 4, 5, 6, and 9 with equal potency in the nM range and was selective against kinases other than Cdks. This compound inhibited multiple events in the cell cycle in vitro, including retinoblastoma protein (pRb) phosphorylation, E2F-dependent transcription, DNA replication (determined by bromodeoxyuridine incorporation), and mitosis completion (assayed by flow cytometry) in the 10 nM range. Moreover, this compound induced cell death, as determined by induction of the subG1 fraction, activated caspase-3, and anexin V. In vivo, Compound M showed anti-tumor efficacy at a tolerated dose. In a nude rat xenograft tumor model, an 8-h constant infusion of Compound M inhibited pRb phosphorylation and induced apoptosis in tumor cells at ~ 30 nM, which led to the inhibition of tumor growth. Immunosuppression was the only liability observed at this dose, but immune function returned to normal after 10 days. Suppression of pRb phosphorylation in tumor cells was clearly correlated with tumor cell growth inhibition and cell death in vitro and in vivo. In vivo, Compound M inhibited pRb phosphorylation in both tumor and gut crypt cells. Rb phosphorylation may be a suitable pharmacodynamic biomarker in both tumors and normal tissues for monitoring target engagement and predicting the efficacy of Compound M. |
| Databáze: | OpenAIRE |
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