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
  • 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.