Small- molecule disruption of androgen receptor-dependent chromatin clusters

• 成果类型: Article
• 署名作者: Kohrt, Sarah E.; Novak, Emily J.; Tapadar, Subhashish; Wu, Bocheng; Strope, Jonathan; Strope, Jonathan; Asante, Yaw; Kim, Hyunmin; Chang, Matthew S.; Gurdak, Douglas; Khalil, Athar; Rood, Michael; Raftery, Eric; Stavreva, Diana; Nguyen, Holly M.; Brown, Lisha G.; Ramser, Maddy; Peer, Cody; Meyers, Warren M.; Aboreden, Nicholas; Chakravortee, Maharshi; Sallari, Richard; Nelson, Peter S.; Kelly, Kathleen K.; Graham, Thomas G. W.; Darzacq, Xavier; Figg, William D.; Oyelere, Adegboyega K.; Corey, Eva; Ogala, Remi Adelaiye --; Gryder, Berkley E.
• 署名单位: University System of Ohio; Case Western Reserve University; University System of Ohio; Case Western Reserve University; University System of Georgia; Georgia Institute of Technology; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI); University System of Ohio; Case Western Reserve University; University System of Ohio; Case Western Reserve University; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI); University of Washington; University of Washington Seattle; University of British Columbia; University of Pennsylvania; University of Washington; University of Washington Seattle; Fred Hutchinson Cancer Center; Fred Hutchinson Cancer Center; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI); University of California System; University of California Berkeley; State University of New York (SUNY) System; University at Buffalo, SUNY
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-15330
• DOI: 10.1073/pnas.2406239121
• 发表日期: 2024-11-26
• 关键词: prostate-cancer; antiandrogen; resistance; enzalutamide; Mutation; mdv3100; gene

摘要

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.