Open AccessSpirocyclic Thiohydantoin Antagonists of F877L and Wild-Type Androgen Receptor for Castration-Resistant Prostate Cancer
Author(s) -
Zhuming Zhang,
Peter J. Connolly,
Luis Trabalón Escolar,
Christian Rocaboy,
Vineet Pande,
Lieven Meerpoel,
HengKeang Lim,
Jonathan R. Branch,
Janine Ondrus,
Ian Hickson,
Tammy L. Bush,
James R. Bischoff,
Gilles Bignan
Publication year - 2021
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/acsmedchemlett.1c00032
Subject(s) - enzalutamide , androgen receptor , prostate cancer , antiandrogens , cancer research , androgen receptor antagonists , medicine , mutant , wild type , androgen , receptor , pharmacology , cancer , chemistry , endocrinology , biology , biochemistry , hormone , gene
Androgen receptor (AR) transcriptional reactivation plays a key role in the development and progression of lethal castration-resistant prostate cancer (CRPC). Recurrent alterations in the AR enable persistent AR pathway signaling and drive resistance to the treatment of second-generation antiandrogens. AR F877L, a point mutation in the ligand binding domain of the AR, was identified in patients who acquired resistance to enzalutamide or apalutamide. In parallel to our previous structure-activity relationship (SAR) studies of compound 4 (JNJ-pan-AR) and clinical stage compound 5 (JNJ-63576253), we discovered additional AR antagonists that provide opportunities for future development. Here we report a highly potent series of spirocyclic thiohydantoins as AR antagonists for the treatment of the F877L mutant and wild-type CRPC.