Cyclins and Cyclin‐Dependent Kinases: Structure, Biological Functions, and Innovative Targeting Strategies in Cancer
TL;DR
This review critically evaluates recent mechanistic advances in CDK/cyclin biology and their pathological dysregulation across malignancies and highlights 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.
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.