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

摘要

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 identifiedKI-ARv-03as an AR-variant complex binder that reduces AR-driven transcription and proliferation in prostate cancer cells. We deducedKI-ARv-03to be a potent, selective inhibitor of CDK9, an important cofactor for AR, MYC, and other oncogenic transcription factors. Further optimization resulted inKB-0742, an orally bioavailable, selective CDK9 inhibitor with potent anti-tumor activity in CRPC models. In 22Rv1 cells,KB-0742rapidly downregulates nascent transcription, preferentially depleting short half-life transcripts and AR-driven oncogenic programs.In vivo, oral administration ofKB-0742significantly reduced tumor growth in CRPC, supporting CDK9 inhibition as a promising therapeutic strategy to target AR dependence in CRPC.