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Discovery of JNJ-63576253, a next-generation androgen receptor antagonist active against wild-type and clinically relevant ligand binding domain mutations in metastatic castration-resistant prostate cancer

Lookup NU author(s): Professor Ian HicksonORCiD


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© 2021 American Association for Cancer Research.Numerous mechanisms of resistance arise in response to treatment with second-generation androgen receptor (AR) pathway inhibitors in metastatic castration-resistant prostate cancer (mCRPC). Among these, point mutations in the ligand binding domain can transform antagonists into agonists, driving the disease through activation of AR signaling. To address this unmet need, we report the discovery of JNJ-63576253, a next-generation AR pathway inhibitor that potently abrogates AR signaling in models of human prostate adenocarcinoma. JNJ-63576253 is advancing as a clinical candidate with potential effectiveness in the subset of patients who do not respond to or are progressing while on second-generation AR-targeted therapeutics.

Publication metadata

Author(s): Branch JR, Bush TL, Pande V, Connolly PJ, Zhang Z, Hickson I, Ondrus J, Jaensch S, Bischoff JR, Habineza G, van Hecke G, Meerpoel L, Packman K, Parrett CJ, Chong YT, Gottardis MM, Bignan G

Publication type: Article

Publication status: Published

Journal: Molecular Cancer Therapeutics

Year: 2021

Volume: 20

Issue: 5

Pages: 763-774

Online publication date: 01/03/2021

Acceptance date: 25/02/2021

ISSN (print): 1535-7163

ISSN (electronic): 1538-8514

Publisher: American Association for Cancer Research Inc.


DOI: 10.1158/1535-7163.MCT-20-0510

PubMed id: 33649102


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