Inhibitors of cyclin-dependent kinases as cancer therapeutics.
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Date
2017-05-01Author
Whittaker, SR
Mallinger, A
Workman, P
Clarke, PA
Type
Journal Article
Metadata
Show full item recordAbstract
Over the past two decades there has been a great deal of interest in the development of inhibitors of the cyclin-dependent kinases (CDKs). This attention initially stemmed from observations that different CDK isoforms have key roles in cancer cell proliferation through loss of regulation of the cell cycle, a hallmark feature of cancer. CDKs have now been shown to regulate other processes, particularly various aspects of transcription. The early non-selective CDK inhibitors exhibited considerable toxicity and proved to be insufficiently active in most cancers. The lack of patient selection biomarkers and an absence of understanding of the inhibitory profile required for efficacy hampered the development of these inhibitors. However, the advent of potent isoform-selective inhibitors with accompanying biomarkers has re-ignited interest. Palbociclib, a selective CDK4/6 inhibitor, is now approved for the treatment of ER+/HER2- advanced breast cancer. Current developments in the field include the identification of potent and selective inhibitors of the transcriptional CDKs; these include tool compounds that have allowed exploration of individual CDKs as cancer targets and the determination of their potential therapeutic windows. Biomarkers that allow the selection of patients likely to respond are now being discovered. Drug resistance has emerged as a major hurdle in the clinic for most protein kinase inhibitors and resistance mechanism are beginning to be identified for CDK inhibitors. This suggests that the selective inhibitors may be best used combined with standard of care or other molecularly targeted agents now in development rather than in isolation as monotherapies.
Collections
Subject
Animals
Humans
Neoplasms
Cyclin-Dependent Kinases
Antineoplastic Agents
Protein Kinase Inhibitors
Cell Cycle
Cell Proliferation
Drug Design
Molecular Targeted Therapy
Research team
Molecular Drug Resistance
Signal Transduction & Molecular Pharmacology
Language
eng
Date accepted
2017-02-05
License start date
2017-05
Citation
Pharmacology & therapeutics, 2017, 173 pp. 83 - 105
Publisher
PERGAMON-ELSEVIER SCIENCE LTD