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.
André Richters  1 ,  Shelby K Doyle  2 ,  David B Freeman  3 ,  Christina Lee  3 ,  Becky S Leifer  1 ,  Sajjeev Jagannathan  4 ,  Florian Kabinger  1 ,  Jošt Vrabič Koren  4 ,  Nicholas B Struntz  1 ,  Julie Urgiles  5 ,  Ryan A Stagg  6 ,  Brice H Curtin  1 ,  Deep Chatterjee  7 ,  Sebastian Mathea  7 ,  Peter J Mikochik  3 ,  Tamara D Hopkins  3 ,  Hua Gao  3 ,  Jonathan R Branch  8 ,  Hong Xin  8 ,  Lori Westover  8 ,  Gilles C Bignan  8 ,  Brent A Rupnow  8 ,  Kristen L Karlin  4 ,  Calla M Olson  4 ,  Thomas F Westbrook  4 ,  Joseph Vacca  3 ,  Chris M Wilfong  3 ,  B Wesley Trotter  3 ,  Douglas C Saffran  3 ,  Norbert Bischofberger  3 ,  Stefan Knapp  7 ,  Joshua W Russo  9 ,  Ian Hickson  10 ,  James R Bischoff  8 ,  Marco M Gottardis  8 ,  Steven P Balk  9 ,  Charles Y Lin  11 ,  Marius S Pop  3 ,  Angela N Koehler  12
Affiliations
  • 1. David 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.
  • 2. David 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; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
  • 3. Kronos Bio, Inc., Cambridge, MA 02139, USA.
  • 4. Therapeutic Innovation Center, Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
  • 5. David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Harvard-MIT Health Sciences and Technology, Boston, MA 02115, USA.
  • 6. David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Department of Biology, Boston University, Boston, MA 02215, USA.
  • 7. Goethe-Universität Frankfurt, 60438 Frankfurt am Main, Germany.
  • 8. Janssen Research & Development, LLC, Spring House, PA, USA.
  • 9. Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
  • 10. Janssen Research & Development, LLC, Spring House, PA, USA; Cancer Research UK Newcastle Drug Discovery Unit, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
  • 11. Kronos Bio, Inc., Cambridge, MA 02139, USA; Therapeutic Innovation Center, Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
  • 12. David 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; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Electronic address: [email protected].
PMID: 33086052 DOI: 10.1016/j.chembiol.2020.10.001
Abstract

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.
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