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.
Keywords: androgen receptor; chromatin architecture; epigenetics; gene regulation; prostate cancer.