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Cell Chem Biol DOI:10.1016/j.chembiol.2020.10.001

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

Publication TypeJournal Article
Year of Publication2021
AuthorsRichters, A, Doyle, SK, Freeman, DB, Lee, C, Leifer, BS, Jagannathan, S, Kabinger, F, Koren, JVrabič, Struntz, NB, Urgiles, J, Stagg, RA, Curtin, BH, Chatterjee, D, Mathea, S, Mikochik, PJ, Hopkins, TD, Gao, H, Branch, JR, Xin, H, Westover, L, Bignan, GC, Rupnow, BA, Karlin, KL, Olson, CM, Westbrook, TF, Vacca, J, Wilfong, CM, B Trotter, W, Saffran, DC, Bischofberger, N, Knapp, S, Russo, JW, Hickson, I, Bischoff, JR, Gottardis, MM, Balk, SP, Lin, CY, Pop, MS, Koehler, AN
JournalCell Chem Biol
Date Published2021 Feb 18

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.


Alternate JournalCell Chem Biol
PubMed ID33086052