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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.
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
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
PubMed id: 33086052
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