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

Lookup NU author(s): Professor Ian HicksonORCiD



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Castration-resistant prostate cancers (CRPCs) lose sensitivity to androgen-deprivation therapies butfrequently remain dependent on oncogenic transcription driven by the androgen receptor (AR) and its splicevariants. To discover modulators of AR-variant activity, we used a lysate-based small-molecule microarrayassay and identified KI-ARv-03 as an AR-variant complex binder that reduces AR-driven transcription andproliferation 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 resultedin KB-0742, an orally bioavailable, selective CDK9 inhibitor with potent anti-tumor activity in CRPC models. In22Rv1 cells, KB-0742 rapidly downregulates nascent transcription, preferentially depleting short half-lifetranscripts and AR-driven oncogenic programs. In vivo, oral administration of KB-0742 significantly reducedtumor growth in CRPC, supporting CDK9 inhibition as a promising therapeutic strategy to target AR dependencein CRPC.

Publication metadata

Author(s): Richters A, Doyle SK, Freeman DB, Lee C, Leifer BS, Jagannathan S, Kabinger F, Koren JV, 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, Trotter BW, Saffran DC, Bischofberger N, Knapp S, Russo JW, Hickson I, Bischoff JR, Gottardis MM, Balk SP, Lin CY, Pop MS, Koehler AN

Publication type: Article

Publication status: Published

Journal: Cell Chemical Biology

Year: 2021

Volume: 28

Pages: 1-14

Print publication date: 21/01/2021

Online publication date: 20/10/2020

Acceptance date: 30/09/2020

Date deposited: 15/12/2020

ISSN (electronic): 2451-9448

Publisher: Elsevier


DOI: 10.1016/j.chembiol.2020.10.001

PubMed id: 33086052


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