2006
DOI: 10.1158/0008-5472.can-05-2507
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Discovery and Evaluation of Dual CDK1 and CDK2 Inhibitors

Abstract: In eukaryotic cells, cyclin-dependent kinase (CDK) complexes regulate the temporal progression of cells through the cell cycle. Deregulation in the cell cycle is an essential component in the evolution of cancer. Here, we validate CDK1 and CDK2 as potential therapeutic targets using novel selective smallmolecule inhibitors of cyclin B1/CDK1 and cyclin E2/CDK2 enzyme complexes (CDKi). Flow cytometry-based methods were developed to assess intracellular retinoblastoma (Rb) phosphorylation to show inhibition of th… Show more

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Cited by 70 publications
(62 citation statements)
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“…Newergeneration compounds, such as R547 (35) and P276-00 (36) from Hoffmann-La Roche and Nicholas Piramal, exhibited maximal in vivo growth inhibitions of 60% and 80%, respectively, in several models; but again, no regressions were reported. Similarly, CDKi-277 from Amgen was reported to give cytostasis with regressions observed only at nontolerated doses (37). The antitumor effects of AT7519 continued after treatment ended, with the duration of the off-treatment effect being dependent on the initial size of the tumor and duration and frequency of the dose level administered.…”
Section: Discussionmentioning
confidence: 98%
“…Newergeneration compounds, such as R547 (35) and P276-00 (36) from Hoffmann-La Roche and Nicholas Piramal, exhibited maximal in vivo growth inhibitions of 60% and 80%, respectively, in several models; but again, no regressions were reported. Similarly, CDKi-277 from Amgen was reported to give cytostasis with regressions observed only at nontolerated doses (37). The antitumor effects of AT7519 continued after treatment ended, with the duration of the off-treatment effect being dependent on the initial size of the tumor and duration and frequency of the dose level administered.…”
Section: Discussionmentioning
confidence: 98%
“…Cdk2 siRNA does not interfere with proliferation of several colon cancer cell lines or U2OS osteosarcoma cells (Tetsu and McCormick, 2003;Cai et al, 2006;Payton et al, 2006). In contrast, Cdk2 siRNA delays G1 progression in NCI-H1299 non-small cell lung cancer cells (Cai et al, 2006), induces G1 arrest in melanoma cells (Du et al, 2004) and results in accumulation of HT29 colon cancer cells in S and G2/M phases (Moffat et al, 2006).…”
Section: Silencing Of Cdks In Cell Linesmentioning
confidence: 99%
“…This confirms the mutual compensation between Cdk1 and Cdk2. Using Roscovitine, or even more specific Cdk1/2 inhibitors, also leads to cell-cycle arrest or apoptosis in several cell lines (Payton et al, 2006;Ribas et al, 2006;Wesierska-Gadek et al, 2006). Surprisingly, Roscovitine can also protect thymocytes against apoptosis, and several groups suggest that Cdk2 might be required in these cells for programmed cell death (Gil-Gomez et al, 1998;Hakem et al, 1999).…”
Section: Compound Mouse Mutantsmentioning
confidence: 99%
“…1 The eukaryotic cell cycle progression is driven by cyclin-dependent kinases (CDKs) and negatively regulated by CDK inhibitors (CDKIs). 2,3 In tumor cells, it seen frequently that abnormal function of CDKIs can cause the deregulation of proliferative activity. 4 The p27, a CDKI belonging to the ciprofloxacin/kinase inhibitor protein family, inhibits the CDK2-cyclin E complex and regulates the cell cycle checkpoint at the G1-to-S transition, and it is a putative tumor suppressor.…”
Section: Introductionmentioning
confidence: 99%