1. Academic Validation
  2. Modulating Androgen Receptor-Driven Transcription in Prostate Cancer with Selective CDK9 Inhibitors

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

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].
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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