The DOI matches its Crossref record; 285 of the 292 references it cites were found in a registry or an index.
Inhibitors of cyclin-dependent kinases as cancer therapeutics.
Open accessAbstract
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.
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“This leads to inhibition of phosphorylation of the RB family of proteins and subsequent association with E2Fs and formation of the DREAM complex thereby leading to a cell cycle arrest (Chen et al., 1996; Whittaker et al., 2017; Wiedemeyer, 2018).”
From Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype (2021) · cites this paper as Whittaker et al., 2017
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Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype
Kumari, R., & Jat, P. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.645593 · Cited by 1,622
Matthews, H. K., Bertoli, C., & de Bruin, R. A. M. (2022) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-021-00404-3 · Cited by 1,506
The broken cycle: E2F dysfunction in cancer
Kent, L. N., & Leone, G. W. (2019) · Nature reviews. Cancer · doi:10.1038/s41568-019-0143-7 · Cited by 807
Off-target toxicity is a common mechanism of action of cancer drugs undergoing clinical trials
Lin, A., Giuliano, C. J., Palladino, A. C., John, K. M., Abramowicz, C., Yuan, M. L., Sausville, E. L., Lukow, D. A., Liu, L., Chait, A. R., et al. (2019) · Science Translational Medicine · doi:10.1126/scitranslmed.aaw8412 · Cited by 769
Ding, L., Cao, J., Lin, W.-S., Chen, H., Xiong, X., Ao, H., Yu, M., Lin, J., & Cui, Q. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21061960 · Cited by 655
Metadata
- Authors
- Whittaker, S. R., Mallinger, A., Workman, P., & Clarke, P. A.
- Affiliations
- Institute of Cancer Research (GB)
- Corresponding author
- Clarke, Paul A.
- Venue
- Pharmacology & Therapeutics
- Publisher
- Elsevier BV
- Published
- 2017-05
- Volume
- 173
- Pages
- 83-105
- ISSN
- 0163-7258 (ISSN-L)
- PMC
- PMC6141011
- OpenAlex
- W2583136106
- Cited by
- 384
- References
- 292
- Citations by year
- 2026: 25 · 2025: 38 · 2024: 37 · 2023: 47 · 2022: 38 · 2021: 53 · 2020: 55 · 2019: 51 · 2018: 25 · 2017: 15
- FWCI
- 7.38
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Pharmacology & Therapeutics (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Cancer Research UK (C309/A11566, C368/A6743, A368/A7990)
- Topics
- Health Sciences › Medicine › Oncology › Advanced Breast Cancer Therapies
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Keywords
- cyclin-dependent kinases, cyclin-dependent kinase inhibitors, isoform-selective inhibitors, CDK4/6 inhibitors, palbociclib, breast cancer, cell cycle regulation, tumor cell proliferation, biomarkers, drug resistance, combination therapy, protein kinase inhibitors
- MeSH terms
- Animals, Antineoplastic Agents, Cell Cycle, Humans, Neoplasms, Drug Design, Cyclin-Dependent Kinases, Protein Kinase Inhibitors, Cell Proliferation, Molecular Targeted Therapy
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