2. Academic Validation
  3. Spirocyclic Thiohydantoin Antagonists of F877L and Wild-Type Androgen Receptor for Castration-Resistant Prostate Cancer

Spirocyclic Thiohydantoin Antagonists of F877L and Wild-Type Androgen Receptor for Castration-Resistant Prostate Cancer

  • ACS Med Chem Lett. 2021 Jun 29;12(8):1245-1252. doi: 10.1021/acsmedchemlett.1c00032.
Zhuming Zhang 1,  Peter J Connolly 1,  Luis Trabalón Escolar 2,  Christian Rocaboy 2,  Vineet Pande 3,  Lieven Meerpoel 3,  Heng-Keang Lim 1,  Jonathan R Branch 1,  Janine Ondrus 1,  Ian Hickson 1,  Tammy L Bush 1,  James R Bischoff 1,  Gilles Bignan 1
Affiliations

Affiliations

  • 1 Janssen Research and Development, Spring House, Pennsylvania 19477, United States.
  • 2 Eurofins Villapharma, 30320 Fuente Alamo, Murcia 30320, Spain.
  • 3 Janssen Research and Development, Turnhoutseweg 30, B-2340 Beerse, Belgium.
PMID: 34422225 DOI: 10.1021/acsmedchemlett.1c00032
Abstract

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.

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