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  • 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 chemical biology (2020-10-22)
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
PMID33086052
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.