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

André Richters; Shelby K Doyle; David B Freeman; Christina Lee; Becky S Leifer; Sajjeev Jagannathan; Florian Kabinger; Jošt Vrabič Koren; Nicholas B Struntz; Julie Urgiles; Ryan A Stagg; Brice H Curtin; Deep Chatterjee; Sebastian Mathea; Peter J Mikochik; Tamara D Hopkins; Hua Gao; Jonathan R Branch; Hong Xin; Lori Westover; Gilles C Bignan; Brent A Rupnow; Kristen L Karlin; Calla M Olson; Thomas F Westbrook; Joseph Vacca; Chris M Wilfong; B Wesley Trotter; Douglas C Saffran; Norbert Bischofberger; Stefan Knapp; Joshua W Russo; Ian Hickson; James R Bischoff; Marco M Gottardis; Steven P Balk; Charles Y Lin; Marius S Pop; Angela N Koehler

doi:10.1016/j.chembiol.2020.10.001

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.

Authors

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: [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.

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*

Substances

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

Abstract

Publication types

MeSH terms

Substances

Grants and funding