Modulating Androgen Receptor-Driven Transcription in Prostate Cancer with Selective CDK9 Inhibitors
André Richters, Shelby K. Doyle, David B. Freeman, Christina Lee, Becky Leifer, Sajjeev Jagannathan, Florian Kabinger, Jošt Vrabič Koren, Nicholas B. Struntz, Julie Urgiles, Ryan A. Stagg, Brice H. Curtin, Deep Chatterjee, Sebastian Mathea, Peter Mikochik, Tamara D. Hopkins, Hua Gao, Jonathan R. Branch, Hong Xin, Lori Westover, Gilles Bignan, Brent Rupnow, Kristen L. Karlin, Calla M. Olson, Thomas F. Westbrook, Joseph P. 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
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.