1区 · 生物学
Article
作者: Mikochik, Peter J ; Bignan, Gilles C ; Russo, Joshua W ; Karlin, Kristen L ; Saffran, Douglas C ; Westbrook, Thomas F ; Koehler, Angela N ; Hopkins, Tamara D ; Branch, Jonathan R ; Rupnow, Brent A ; Curtin, Brice H ; Freeman, David B ; Stagg, Ryan A ; Mathea, Sebastian ; Richters, André ; Vacca, Joseph ; Koren, Jošt Vrabič ; Kabinger, Florian ; Bischoff, James R ; Wilfong, Chris M ; Lin, Charles Y ; Urgiles, Julie ; Lee, Christina ; Westover, Lori ; Hickson, Ian ; Trotter, B Wesley ; Olson, Calla M ; Doyle, Shelby K ; Struntz, Nicholas B ; Balk, Steven P ; Gottardis, Marco M ; Xin, Hong ; Pop, Marius S ; Gao, Hua ; Jagannathan, Sajjeev ; Knapp, Stefan ; Bischofberger, Norbert ; Chatterjee, Deep ; Leifer, Becky S
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.