The promise and current status of CDK12/13 inhibition for the treatment of cancer

Future Med Chem. 2021 Jan;13(2):117-141. doi: 10.4155/fmc-2020-0240. Epub 2020 Dec 9.


CDK12 and CDK13 are Ser/Thr protein kinases that regulate transcription and co-transcriptional processes. Genetic silencing of CDK12 is associated with genomic instability in a variety of cancers, including difficult-to-treat breast, ovarian, colorectal, brain and pancreatic cancers, and is synthetic lethal with PARP, MYC or EWS/FLI inhibition. CDK13 is amplified in hepatocellular carcinoma. Consequently, selective CDK12/13 inhibitors constitute powerful research tools as well as promising anti-cancer therapeutics, either alone or in combination therapy. Herein the authors discuss the role of CDK12 and CDK13 in normal and cancer cells, describe their utility as a biomarker and therapeutic target, review the medicinal chemistry optimization of existing CDK12/13 inhibitors and outline strategies for the rational design of CDK12/13 selective inhibitors.

Keywords: CDK12; CDK13; CTD; RNA polymerase II; biomarkers; cancer; chemical probes; inhibitors; therapeutic targets; transcription.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / pharmacology
  • Biomarkers, Tumor / metabolism*
  • Combined Modality Therapy
  • Cyclin-Dependent Kinases / antagonists & inhibitors*
  • Drug Screening Assays, Antitumor
  • Gene Expression Regulation
  • Humans
  • Neoplasms / drug therapy*
  • Protein Binding
  • Protein Conformation
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacology
  • RNA Polymerase II / genetics
  • RNA Polymerase II / metabolism
  • Structure-Activity Relationship


  • Antineoplastic Agents
  • Biomarkers, Tumor
  • Protein Kinase Inhibitors
  • Cyclin-Dependent Kinases
  • RNA Polymerase II