Small-molecule disruption of androgen receptor–dependent chromatin clusters
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.
Authors
- Holly M. Nguyen (ORCID: https://orcid.org/0000-0002-6331-8089)
- Bocheng Wu (ORCID: https://orcid.org/0000-0002-7381-9506)
- Maddy Ramser
- Nicholas Aboreden (ORCID: https://orcid.org/0000-0002-4154-048X)
- Eva Corey (ORCID: https://orcid.org/0000-0002-9244-3807)
- Sarah E. Kohrt (ORCID: https://orcid.org/0000-0002-9754-8894)
- Cody J. Peer (ORCID: https://orcid.org/0000-0001-9395-3473)
- Athar Khalil (ORCID: https://orcid.org/0000-0002-4072-6143)
- Richard Sallari (ORCID: https://orcid.org/0000-0002-5519-2965)
- Eric D. Raftery
- Thomas G.W. Graham (ORCID: https://orcid.org/0000-0001-5189-4313)
- Adegboyega K. Oyelere (ORCID: https://orcid.org/0000-0002-2248-9551)
- Kathleen Kelly (ORCID: https://orcid.org/0000-0002-1102-6279)
- Jonathan D. Strope (ORCID: https://orcid.org/0000-0001-8247-8427)
- EK Novak (ORCID: https://orcid.org/0000-0003-2828-9187)
- Michael P. Rood
- Maharshi Chakraborty (ORCID: https://orcid.org/0000-0003-2898-4710)
- Warren M. Meyers (ORCID: https://orcid.org/0000-0003-2649-9324)
- Peter S. Nelson (ORCID: https://orcid.org/0000-0002-5451-5726)
- Diana A. Stavreva (ORCID: https://orcid.org/0000-0002-7904-6452)
- Xavier Darzacq (ORCID: https://orcid.org/0000-0003-2537-8395)
- Remi Adelaiye‐Ogala (ORCID: https://orcid.org/0000-0002-6581-7359)
- William D. Figg (ORCID: https://orcid.org/0000-0003-2428-5613)
- Subhashish Tapadar
- Berkley E. Gryder (ORCID: https://orcid.org/0000-0003-0130-2302)
- Lisha G. Brown (ORCID: https://orcid.org/0009-0009-7262-2080)
- Yaw Asante (ORCID: https://orcid.org/0000-0002-6924-8632)
- Hyunmin Kim (ORCID: https://orcid.org/0000-0001-7005-2568)
- D. Gurdak
- Matthew S. Chang
Institutions
- Georgia Institute of Technology (US)
- University of British Columbia (CA)
- University of Washington (US)
- Fred Hutch Cancer Center (US)
- National Cancer Institute (US)
- Center for Cancer Research (US)
- University School (US)
- Case Western Reserve University (US)
- University at Buffalo, State University of New York (US)
- University of Pennsylvania (US)
- University of California, Berkeley (US)
Publication Details
- Journal
- Proceedings of the National Academy of Sciences
- Published
- 2024-11-19
- DOI
- https://doi.org/10.1073/pnas.2406239121
- Citations
- 3
- Primary Topic
- Prostate Cancer Treatment and Research
- Type
- article
- Field-Weighted Citation Impact
- 1.26
Funders
- U.S. Department of Defense
- Prostate Cancer Foundation
- Georgia Institute of Technology
- University of Pennsylvania
- Itä-Suomen Yliopisto
- University of Washington
- Case Western Reserve University
- Case Comprehensive Cancer Center, Case Western Reserve University
- School of Medicine, Case Western Reserve University
- Kaleida Health Foundation
- Universitat de Barcelona
- Institute for Bioengineering and Biosciences
- National Institutes of Health
- Perelman School of Medicine, University of Pennsylvania
- University at Buffalo
- National Cancer Institute