Dissecting the Pol II transcription cycle and derailing cancer with CDK inhibitors

Nat Chem Biol. 2020 Jul;16(7):716-724. doi: 10.1038/s41589-020-0563-4. Epub 2020 Jun 22.

Abstract

Largely non-overlapping sets of cyclin-dependent kinases (CDKs) regulate cell division and RNA polymerase II (Pol II)-dependent transcription. Here we review the molecular mechanisms by which specific CDKs are thought to act at discrete steps in the transcription cycle and describe the recent emergence of transcriptional CDKs as promising drug targets in cancer. We emphasize recent advances in understanding the transcriptional CDK network that were facilitated by development and deployment of small-molecule inhibitors with increased selectivity for individual CDKs. Unexpectedly, several of these compounds have also shown selectivity in killing cancer cells, despite the seemingly universal involvement of their target CDKs during transcription in all cells. Finally, we describe remaining and emerging challenges in defining functions of individual CDKs in transcription and co-transcriptional processes and in leveraging CDK inhibition for therapeutic purposes.

Publication types

  • Research Support, N.I.H., Extramural
  • Review

MeSH terms

  • Animals
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Cell Cycle Checkpoints / drug effects
  • Cell Cycle Checkpoints / genetics
  • Cyclin-Dependent Kinases / antagonists & inhibitors*
  • Cyclin-Dependent Kinases / genetics
  • Cyclin-Dependent Kinases / metabolism
  • Disease Models, Animal
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Neoplasms / drug therapy*
  • Neoplasms / enzymology
  • Neoplasms / genetics
  • Neoplasms / pathology
  • Proteasome Endopeptidase Complex / metabolism
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Proteolysis
  • RNA Polymerase II / antagonists & inhibitors
  • RNA Polymerase II / genetics*
  • RNA Polymerase II / metabolism
  • Signal Transduction
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology*
  • Transcription, Genetic

Substances

  • Antineoplastic Agents
  • Protein Kinase Inhibitors
  • Small Molecule Libraries
  • Cyclin-Dependent Kinases
  • RNA Polymerase II
  • Proteasome Endopeptidase Complex