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Discovery of JNJ-63576253: A Clinical Stage Androgen Receptor Antagonist for F877L Mutant and Wild-Type Castration-Resistant Prostate Cancer (mCRPC)

Lookup NU author(s): Professor Ian HicksonORCiD



This is the authors' accepted manuscript of an article that has been published in its final definitive form by American Chemical Society, 2021.

For re-use rights please refer to the publisher's terms and conditions.


Persistent androgen receptor (AR) activation drives therapeutic resistance to second-generation AR pathway inhibitors and contributes to the progression of advanced prostate cancer. One resistance mechanism is point mutations in the ligand binding domain of AR that can transform antagonists into agonists. The AR F877L mutation, identified in patients treated with enzalutamide or apalutamide, confers resistance to both enzalutamide and apalutamide. Compound 4 (JNJ-pan-AR) was identified as a pan-AR antagonist with potent activity against wild-type and clinically relevant AR mutations including F877L. Metabolite identification studies revealed a latent bioactivation pathway associated with 4. Subsequent lead optimization of 4 led to amelioration of this pathway and nomination of 5 (JNJ-63576253) as a clinical stage, next-generation AR antagonist for the treatment of castration-resistant prostate cancer (CRPC).

Publication metadata

Author(s): Zhang Z, Connolly PJ, Lim HK, Pande V, Meerpoel L, Teleha C, Branch JR, Ondrus J, Hickson I, Bush T, Luistro L, Packman K, Bischoff JR, Ibrahim S, Parrett C, Chong Y, Gottardis MM, Bignan G

Publication type: Article

Publication status: Published

Journal: Journal of Medicinal Chemistry

Year: 2021

Volume: 64

Issue: 2

Pages: 909-924

Print publication date: 28/01/2021

Online publication date: 20/01/2021

Acceptance date: 07/09/2020

Date deposited: 26/03/2021

ISSN (print): 0022-2623

ISSN (electronic): 1520-4804

Publisher: American Chemical Society


DOI: 10.1021/acs.jmedchem.0c01563


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