Regression of Castrate-Recurrent Prostate Cancer by a Small-Molecule Inhibitor of the Amino-Terminus Domain of the Androgen Receptor

Abstract

Castration-recurrent prostate cancer (CRPC) is suspected to depend on androgen receptor (AR). The AF-1 region in the amino-terminal domain (NTD) of AR contains most, if not all, of the transcriptional activity. Here we identify EPI-001, a small molecule that blocked transactivation of the NTD and was specific for inhibition of AR without attenuating transcriptional activities of related steroid receptors. EPI-001 interacted with the AF-1 region, inhibited protein-protein interactions with AR, and reduced AR interaction with androgen-response elements on target genes. Importantly, EPI-001 blocked androgen-induced proliferation and caused cytoreduction of CRPC in xenografts dependent on AR for growth and survival without causing toxicity.

Selectively Targeting the DNA-binding Domain of the Androgen Receptor as a Prospective Therapy for Prostate Cancer

“…4D) could be achieved. These levels of inhibition are similar to that of EPI-001, which could achieve ϳ80% inhibition of the AR(1-653) truncation mutant, lacking the LBD, when tested at 25 M concentration on PC3 cells co-transfected with ARR 3 tk-luciferase reporter (44).…”

Structure-based Virtual Screening and Identification of a Novel Androgen Receptor Antagonist

“…Recent studies have shown that resveratrol, EPI-001, RD162, and MDV3100 also have the ability to inhibit both androgenindependent and androgen-dependent proliferation in prostate cancer cells (71,76,87). Resveratrol and EPI-001 have been shown to inhibit the growth of androgen-independent prostate cancer cells by negatively regulating PI3K/AKT pathway-activated AR activity.…”

NDRG2 acts as a negative regulator downstream of androgen receptor and inhibits the growth of androgen-dependent and castration-resistant prostate cancer

“…12 In addition, tumors that are refractory to conventional androgen deprivation therapy are susceptible to more potent androgen pathway inhibitors. 13,14 These studies strongly indicate that AR signaling continues to play a significant role in CRPC. Thus, more comprehensive understanding of the regulation of the AR axis and the development of novel AR signaling-targeting therapies is imperative in this field.…”