Targeting CDKs in the RNAPII transcription cycle.

Cyclin-dependent kinases (CDKs) are central regulators of both the cell division cycle and RNA polymerase II (RNAPII)-mediated transcription and have long been pursued as therapeutic targets in cancer and other diseases. Although drug discovery efforts have historically focused on cell-cycle CDKs, transcriptional CDKs have emerged in the past 10-15 years as promising therapeutic candidates. In this Review, we discuss our current understanding of how CDKs regulate gene expression throughout all stages of transcription from initiation and elongation to termination and beyond. We examine how transcriptional or co-transcriptional processes become dysregulated in cancer cells, and how this dysfunction might create targetable vulnerabilities. We also summarize advances in therapeutic strategies targeting transcriptional CDKs, including reversible and covalent inhibitors, degraders, molecular glues and bivalent proximity-inducing modalities such as transcriptional and epigenetic chemical inducers of proximity, which can rewire transcriptional networks in vivo. Finally, we highlight the key mechanistic, translational and clinical challenges that must be addressed to realise the therapeutic potential of targeting transcriptional CDKs in cancer and inflammation.