Small Molecule CDK Inhibitors for the Therapeutic Management of Cancer
Bharat Goel1, Nancy Tripathi1, Nivedita Bhardwaj1
1Department of Pharmaceutical Engineering and Technology, Indian Institute of Technology (Banaras Hindu University), Varanasi-221005, India.
Abstract:
Cyclin-dependent kinases (CDKs) are a group of multifunctional enzymes consisting of catalytic and regulatory subunits. The regulatory subunit, cyclin, remains dissociated under normal circumstances, and complexation of cyclin with the catalytic subunit of CDK leads to its activation for phosphorylation of protein substrates. The primary role of CDKs is in the regulation of the cell cycle. Retinoblastoma protein (Rb) is one of the widely investigated tumor suppressor protein substrates of CDK, which prevents cells from entering into cell-cycle under normal conditions. Phosphorylation of Rb by CDKs causes its inactivation and ultimately allows cells to enter a new cell cycle. Many cancers are associated with hyperactivation of CDKs as a result of mutation of the CDK genes or CDK inhibitor genes. Therefore, CDK modulators are of great interest to explore as novel therapeutic agents against cancer and led to the discovery of several CDK inhibitors to clinics. This review focuses on the current progress and development of anti-cancer CDK inhibitors from preclinical to clinical and synthetic to natural small molecules.
Insights
Cyclin-dependent kinases (CDKs) regulate the cell cycle by phosphorylating proteins like Retinoblastoma protein (Rb). Inhibiting aberrant CDK activity shows promise for novel anti-cancer therapeutics.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Cyclin-dependent kinases (CDKs) are crucial enzymes regulating the cell cycle via catalytic and cyclin subunits.
- CDKs phosphorylate substrates like the Retinoblastoma protein (Rb), a tumor suppressor that normally halts cell division.
- Dysregulation of CDK activity is implicated in various cancers, making them therapeutic targets.
Purpose of the Study:
- To review the progress and development of anti-cancer CDK inhibitors.
- To explore both synthetic and natural small molecules targeting CDKs.
- To cover the journey from preclinical research to clinical applications of CDK inhibitors.
Main Methods:
- Literature review of preclinical and clinical studies on CDK inhibitors.
- Analysis of synthetic and natural small molecules targeting CDK pathways.
- Focus on the mechanism of CDK-mediated phosphorylation and its role in cancer.
Main Results:
- CDK inhibitors have advanced from preclinical stages to clinical trials.
- Various small molecules, both synthetic and natural, are being investigated for anti-cancer properties.
- Targeting CDK activity represents a significant therapeutic strategy in oncology.
Conclusions:
- CDK inhibitors are a promising class of anti-cancer agents.
- Continued research into CDK modulators is vital for developing new cancer therapies.
- The development pipeline includes diverse molecules with potential clinical impact.
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