Targeting Cyclin-Dependent Kinases (CDKs) for Cancer Therapy: An In-Depth Review of Molecular Candidates, Their Synthesis, Evaluation, and Future Directions

Cyclin-dependent kinases (CDKs) are ser/thr kinases that affect cell cycle progression by phosphorylation of target substrates in a regulated manner. The catalytic mechanisms of these enzymes operate in complex with regulatory cyclin subunits. Their activities are tightly controlled by CKIs and phosphorylation events. The mechanisms of malignant transformation that affect CDK include cyclin overexpression, CKI loss, alteration of upstream signaling pathways, and failure to trigger the compensatory mechanisms necessary to inhibit CDK activity. Ultimately, this results in the disruption of the cell cycle, which leads to dysregulation of cellular proliferation and genomic instability. This comprehensive review focuses on the current status of CDK-targeted cancer therapeutics and the types of principles and mechanisms employed in structure-based drug design. We review how CDK4/6 inhibitors (palbociclib, ribociclib, and abemaciclib) in hormone receptor-positive breast cancer have changed treatment paradigms and the proof of concept for selective CDK targeting as a therapeutic strategy. The acquisition of resistance, however, is not without challenges - alterations to the Rb pathway, upregulation of cyclin E1, and activation of alternative signaling network PI3K/mTOR and RTK/RAS pathways. We present a critical review of recent strategies to overcome resistance, including rational drug combination therapy, new generation inhibitors of alternative isoforms of CDKs (CDK2, CDK7, CDK9, and CDK12), and novel approaches applying PROTACs and molecular glue therapies to lead to degradation of CDK proteins. In addition, biomarker-based patient stratification is examined for harnessing precision medicine in drug delivery outcomes. The development of CDK inhibitors currently faces challenges in achieving selectivity with potency, off-target toxicities, and predictive biomarkers of response. Future research will examine synthetic lethal interactions, immunological activities following CDK inhibition, and combination with other treatment options including new forms of immunotherapy and epigenetic modulators. This review summarises what we know so far and points out the most promising targets for developing more effective and personalised CDK targeted therapies.

Keywords: Cyclin-dependent kinases (CDKs), CDK4/6 inhibitors, Palbociclib, Ribociclib, Abemaciclib, Cancer therapy, Cell cycle regulation, Drug resistance, Targeted therapy, Structure-based drug design, Biomarkers, Precision medicine

© Farm Pol, 2025, 81(8): 489–499