. 2021 Feb 18;28(2):134-147.e14.

doi: 10.1016/j.chembiol.2020.10.001. Epub 2020 Oct 20.

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

André Richters¹, Shelby K Doyle², David B Freeman³, Christina Lee³, Becky S Leifer¹, Sajjeev Jagannathan⁴, Florian Kabinger¹, Jošt Vrabič Koren⁴, Nicholas B Struntz¹, Julie Urgiles⁵, Ryan A Stagg⁶, Brice H Curtin¹, Deep Chatterjee⁷, Sebastian Mathea⁷, Peter J Mikochik³, Tamara D Hopkins³, Hua Gao³, Jonathan R Branch⁸, Hong Xin⁸, Lori Westover⁸, Gilles C Bignan⁸, Brent A Rupnow⁸, Kristen L Karlin⁴, Calla M Olson⁴, Thomas F Westbrook⁴, Joseph Vacca³, Chris M Wilfong³, B Wesley Trotter³, Douglas C Saffran³, Norbert Bischofberger³, Stefan Knapp⁷, Joshua W Russo⁹, Ian Hickson¹⁰, James R Bischoff⁸, Marco M Gottardis⁸, Steven P Balk⁹, Charles Y Lin¹¹, Marius S Pop³, Angela N Koehler¹²

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: koehler@mit.edu.

PMID: 33086052
DOI: 10.1016/j.chembiol.2020.10.001

Free article

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

André Richters et al. Cell Chem Biol. 2021.

Free article

. 2021 Feb 18;28(2):134-147.e14.

doi: 10.1016/j.chembiol.2020.10.001. Epub 2020 Oct 20.

Authors

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: koehler@mit.edu.

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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Conflict of interest statement

Declaration of Interests A.N.K. is a founder and member of the scientific advisory board of Kronos Bio, Inc. D.B.F., N.B.S., S.K.D., A.R., M.S.P., and A.N.K. are inventors on patent applications related to KI-ARv-03.

Comment in

Blocking the Enablers: Selective Inhibition of CDK9 Reins in an Unchecked Master Regulator.
Ansari AZ. Ansari AZ. Cell Chem Biol. 2021 Feb 18;28(2):113-115. doi: 10.1016/j.chembiol.2021.01.022. Cell Chem Biol. 2021. PMID: 33607002

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

Comment in

Publication types

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Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Molecular Biology Databases

Research Materials

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