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Preclinical and clinical development of cyclin-dependent kinase modulators
A M Senderowicz1, E A Sausville
1DTP Clinical Trials Unit, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD 20892, USA. sendero@helix.nih.gov
Abstract:
In the last decade, the discovery and cloning of the cyclin-dependent kinases (cdks), key regulators of cell cycle progression, have led to the identification of novel modulators of cdk activity. Initial experimental results demonstrated that these cdk modulators are able to block cell cycle progression, induce apoptotic cell death, promote differentiation, inhibit angiogenesis, and modulate transcription. Alteration of cdk activity may occur indirectly by affecting upstream pathways that regulate cdk activity or directly by targeting the cdk holoenzyme. Two direct cdk modulators, flavopiridol and UCN-01, are showing promising results in early clinical trials, in which the drugs reach plasma concentrations that can alter cdk activity in vitro. Although modulation of cdk activity is a well-grounded concept and new cdk modulators are being assessed for clinical testing, important scientific questions remain to be addressed. These questions include whether one or more cdks should be inhibited, how cdk inhibitors should be combined with other chemotherapy agents, and which cdk substrates should be used to assess the biologic effects of these drugs in patients. Thus, modulation of cdk activity is an attractive target for cancer chemotherapy, and several agents that modulate cdk activity are in or are approaching entry into clinical trials.
Insights
Novel modulators of cyclin-dependent kinases (cdks) show promise in cancer therapy by blocking cell cycle progression and inducing apoptosis. Further research is needed to optimize cdk inhibitor use in clinical trials.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Cyclin-dependent kinases (cdks) are crucial regulators of cell cycle progression.
- Dysregulated cdk activity is implicated in cancer development.
- Novel cdk modulators offer potential therapeutic strategies.
Purpose of the Study:
- To review the discovery and therapeutic potential of cdk modulators in cancer.
- To discuss the mechanisms of cdk modulation and their effects.
- To highlight ongoing clinical trials and future research directions.
Main Methods:
- Review of existing literature on cdk discovery and function.
- Analysis of experimental data on cdk modulator effects (e.g., cell cycle arrest, apoptosis, differentiation, angiogenesis inhibition, transcription modulation).
- Examination of early clinical trial results for cdk inhibitors like flavopiridol and UCN-01.
Main Results:
- Cdk modulators can block cell cycle progression, induce apoptosis, promote differentiation, inhibit angiogenesis, and modulate transcription.
- Direct cdk modulators flavopiridol and UCN-01 show promising results in early clinical trials.
- Achieved plasma concentrations of these drugs can alter cdk activity in vitro.
Conclusions:
- Modulation of cdk activity is a viable and attractive target for cancer chemotherapy.
- Several cdk modulators are in or nearing clinical trials.
- Key scientific questions remain regarding optimal cdk inhibition strategies, combination therapies, and biomarker development for assessing drug efficacy.