Related Experiment Video

Updated: Dec 4, 2025

A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer
07:25

A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer

Published on: March 6, 2018

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

André Richters1, Shelby K Doyle2, David B Freeman3

  • 1David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; MIT Center for Precision Cancer Medicine, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.

Cell Chemical Biology
|October 21, 2020
PubMed

Insights

A new drug, KB-0742, targets CDK9 to inhibit androgen receptor (AR) activity in castration-resistant prostate cancer (CRPC). This selective CDK9 inhibitor shows potent anti-tumor effects in CRPC models, offering a promising therapeutic strategy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • Castration-resistant prostate cancer (CRPC) remains dependent on androgen receptor (AR) signaling despite resistance to standard therapies.
  • AR splice variants are key drivers of CRPC, necessitating novel therapeutic targets.

Purpose of the Study:

  • To identify small molecules that modulate AR-variant activity.
  • To develop a selective inhibitor of CDK9, a critical cofactor for AR-driven transcription.

Main Methods:

  • Utilized a small-molecule microarray assay to screen for AR-variant modulators.
  • Identified and optimized KI-ARv-03, leading to the development of the selective CDK9 inhibitor KB-0742.
  • Assessed the anti-tumor activity of KB-0742 in CRPC cell lines and in vivo models.

Main Results:

  • KI-ARv-03 was identified as an AR-variant complex binder and CDK9 inhibitor.
  • KB-0742 demonstrated potent and selective inhibition of CDK9, reducing AR-driven transcription and proliferation.
  • Oral administration of KB-0742 significantly inhibited tumor growth in CRPC models.

Conclusions:

  • CDK9 inhibition is a viable therapeutic strategy for targeting AR-dependent CRPC.
  • KB-0742 exhibits promising anti-tumor activity and warrants further clinical investigation for CRPC treatment.
Keywords:
androgen receptorcyclin-dependent kinase 9interactome modulatorsprostate cancersmall molecule microarraytranscription factors

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