Molecular targeting of CDK9 in oncology therapeutics: avenues for translational impact.

CDK4/6 Inhibitors in Breast Cancer: Clinical Applications, Translational Insights, and Future Directions

This review examines the clinical development of palbociclib, ribociclib, and abemaciclib across both early-stage and metastatic settings, revealing clinically meaningful differences in efficacy that challenge the notion of a uniform class effect.

Cyclins and Cyclin‐Dependent Kinases: Structure, Biological Functions, and Innovative Targeting Strategies in Cancer

ABSTRACT Cyclins and cyclin‐dependent kinases (CDKs) are frequently dysregulated in human cancers and represent compelling therapeutic targets. Beyond their well‐recognized roles in cell cycle control, CDK/cyclin complexes orchestrate diverse oncogenic processes, including transcription, genome maintenance, epigenetics, metabolism, and immune regulation. Deciphering the multifaceted biology of CDK/cyclin will provide valuable insights and rationales for the development of CDK/cyclin‐targeting strategies and modalities. While the clinical success of CDK4/6 inhibitors has validated CDKs as druggable targets, further efforts are urgently needed to target other CDKs and cyclins. This review critically evaluates recent mechanistic advances in CDK/cyclin biology and their pathological dysregulation across malignancies. We analyze the paradigm shift from conventional enzymatic inhibition toward proximity‐induced modulation. Specifically, we highlight emerging approaches including proteolysis‐targeting chimeras, HSP90‐mediated targeting chimeras, hydrophobic tagging, molecular glues, and autophagy‐tethering compounds that achieve selective elimination of CDKs or their cyclin partners. In parallel, we summarize strategies designed to redistribute CDK complexes and rewire transcription without enzymatic ablation, referred to as chemical inducers of proximity and transcriptional/epigenetic modulators. By integrating fundamental CDK/cyclin biology with pharmacological innovation in targeted protein degradation and kinase reprogramming, this review provides a timely roadmap for the CDK/cyclin research field and expands the frontiers of CDK/cyclin‐targeted cancer therapy.

Adaptive mechanisms and emerging cancer therapeutics for CDK2 inhibitors.

SKP2 in Cancer: From Molecular Regulation to Therapeutic Vulnerabilities and Translational Perspectives

Emerging evidence has expanded the functional repertoire of SKP2 beyond cell cycle control to encompass metabolism, DNA repair, stemness, tumor microenvironment and immunotherapy response, positioning it as an increasingly attractive target for intervention.

Recent Progress in Targeting Kinases Involved in the DNA Damage Response for the Treatment of Cancer

The therapeutic potential of pharmacologically targeting kinases involved in regulating the DNA damage response (DDR) has been investigated for over two decades. Inhibitors of ATM, ATR, CHK1, CHK2 and WEE1 have been developed with the aim of subverting cell cycle checkpoint function in cancer cells, promoting cell death. The DNA repair pathway non-homologous end-joining can also be targeted through DNA-PK inhibition. However, despite extensive preclinical and clinical studies, none of the many candidate inhibitors have yet made it through to clinical approval. Emerging evidence for tumour biomarkers associated with enhanced sensitivity to DDR kinase inhibition may provide a way through this impasse. Clinical testing in appropriately stratified cohorts is now becoming increasingly common, with some promising results. Building on results obtained with small-molecule inhibitors, targeted protein degradation (TPD) utilising proteolysis-targeting chimaeras (PROTACs) or molecular glues for degradation of DDR kinases is a rapidly developing strategy. This review discusses the current ATM, ATR, DNA-PK, CHK1, CHK2 and WEE1 inhibitors that show the most promise as monotherapies and combination treatments in solid tumours, as well as the potential benefits of using TPD technology over small-molecule inhibitors. Established and emerging biomarkers that can be applied to patient selection are also discussed.

Targeting CDKs in the RNAPII transcription cycle.