Modulating Androgen Receptor-Driven Transcription in Prostate Cancer with Selective CDK9 Inhibitors

Cell Chem Biol. 2021 Feb 18;28(2):134-147.e14. doi: 10.1016/j.chembiol.2020.10.001. Epub 2020 Oct 20.


Castration-resistant prostate cancers (CRPCs) lose sensitivity to androgen-deprivation therapies but frequently remain dependent on oncogenic transcription driven by the androgen receptor (AR) and its splice variants. To discover modulators of AR-variant activity, we used a lysate-based small-molecule microarray assay and identified KI-ARv-03 as an AR-variant complex binder that reduces AR-driven transcription and proliferation in prostate cancer cells. We deduced KI-ARv-03 to be a potent, selective inhibitor of CDK9, an important cofactor for AR, MYC, and other oncogenic transcription factors. Further optimization resulted in KB-0742, an orally bioavailable, selective CDK9 inhibitor with potent anti-tumor activity in CRPC models. In 22Rv1 cells, KB-0742 rapidly downregulates nascent transcription, preferentially depleting short half-life transcripts and AR-driven oncogenic programs. In vivo, oral administration of KB-0742 significantly reduced tumor growth in CRPC, supporting CDK9 inhibition as a promising therapeutic strategy to target AR dependence in CRPC.

Keywords: androgen receptor; cyclin-dependent kinase 9; interactome modulators; prostate cancer; small molecule microarray; transcription factors.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Androgen Receptor Antagonists / pharmacology*
  • Androgen Receptor Antagonists / therapeutic use
  • Animals
  • Cell Line, Tumor
  • Cyclin-Dependent Kinase 9 / antagonists & inhibitors*
  • Cyclin-Dependent Kinase 9 / genetics
  • Gene Expression Regulation, Neoplastic / drug effects
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Models, Molecular
  • Prostatic Neoplasms, Castration-Resistant / drug therapy*
  • Prostatic Neoplasms, Castration-Resistant / genetics
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Kinase Inhibitors / therapeutic use
  • Receptors, Androgen / genetics*
  • Transcription, Genetic / drug effects*


  • Androgen Receptor Antagonists
  • Protein Kinase Inhibitors
  • Receptors, Androgen
  • Cyclin-Dependent Kinase 9