Sustained androgen receptor (AR) signaling during relapse is a central driver of metastatic castration-resistant prostate cancer (mCRPC). Current AR antagonists, such as enzalutamide, fail to provide long-term benefit for the mCRPC patients who have dramatic increases in AR expression. Here, we report AR antagonists with efficacy in AR-overexpressing models. These molecules bind to the ligand-binding domain of the AR, promote AR localization to the nucleus, yet potently and selectively down-regulate AR-target genes. The molecules BG-15a and the pharmacokinetically optimized BG-15n elicit a decrease in cell and tumor growth in vitro and in vivo in models of mCRPC. BG-15a/n treatment causes the collapse of chromatin loops between enhancers and promoters at key genes in the AR-driven epigenome. AR binding in the promoter, as well as 3D chromatin clustering, is needed for genes to respond. BG-15a/n represent promising agents for treating patients with relapsed AR-driven mCRPC tumors.
Proceedings of the National Academy of Sciences of the United States of America. 2024 Nov 19 [Epub]
Sarah E Kohrt, Emily J Novak, Subhashish Tapadar, Bocheng Wu, Jonathan Strope, Yaw Asante, Hyunmin Kim, Matthew S Chang, Douglas Gurdak, Athar Khalil, Michael Rood, Eric Raftery, Diana Stavreva, Holly M Nguyen, Lisha G Brown, Maddy Ramser, Cody Peer, Warren M Meyers, Nicholas Aboreden, Maharshi Chakravortee, Richard Sallari, Peter S Nelson, Kathleen K Kelly, Thomas G W Graham, Xavier Darzacq, William D Figg, Adegboyega K Oyelere, Eva Corey, Remi Adelaiye-Ogala, Berkley E Gryder
Cancer Genomics and Epigenomics Program, Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH 44106., Department of Pharmacology, Case Western Reserve University School of Medicine, Cleveland, OH 44106., Parker H. Petit Institute for Bioengineering and Biosciences, Department of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, GA 30332., Clinical Pharmacology Program, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892., Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, OH 44106., Alphazyme, Jupiter, FL 33458., Laboratory of Receptor Biology and Gene Expression, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892., Department of Urology, University of Washington, Seattle, WA 98195., Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, BC V6T 1Z3, Canada., Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104., Axiotl Inc., Cleveland, OH 44106., Department of Medicine, University of Washington, Seattle, WA 98195., Laboratory for Genitourinary Cancer Pathogenesis, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892., Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720., Division of Hematology and Oncology, Department of Medicine, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY 14203.