An androgen receptor N-terminal domain antagonist for treating prostate cancer
Jae-Kyung Myung, … , Raymond J. Andersen, Marianne D. Sadar
Jae-Kyung Myung, … , Raymond J. Andersen, Marianne D. Sadar
Published June 3, 2013
Citation Information: J Clin Invest. 2013;123(7):2948-2960. https://doi.org/10.1172/JCI66398.
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Research Article Oncology

An androgen receptor N-terminal domain antagonist for treating prostate cancer

Abstract

Hormone therapies for advanced prostate cancer target the androgen receptor (AR) ligand-binding domain (LBD), but these ultimately fail and the disease progresses to lethal castration-resistant prostate cancer (CRPC). The mechanisms that drive CRPC are incompletely understood, but may involve constitutively active AR splice variants that lack the LBD. The AR N-terminal domain (NTD) is essential for AR activity, but targeting this domain with small-molecule inhibitors is complicated by its intrinsic disorder. Here we investigated EPI-001, a small-molecule antagonist of AR NTD that inhibits protein-protein interactions necessary for AR transcriptional activity. We found that EPI analogs covalently bound the NTD to block transcriptional activity of AR and its splice variants and reduced the growth of CRPC xenografts. These findings suggest that the development of small-molecule inhibitors that bind covalently to intrinsically disordered proteins is a promising strategy for development of specific and effective anticancer agents.

Authors

Jae-Kyung Myung, Carmen A. Banuelos, Javier Garcia Fernandez, Nasrin R. Mawji, Jun Wang, Amy H. Tien, Yu Chi Yang, Iran Tavakoli, Simon Haile, Kate Watt, Iain J. McEwan, Stephen Plymate, Raymond J. Andersen, Marianne D. Sadar

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Figure 6

Oral dosing of EPI-002 blocks AR transcriptional program and inhibits growth of VCaP CRPC xenografts that express AR splice variants.

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Oral dosing of EPI-002 blocks AR transcriptional program and inhibits gr...
(A) VCaP tumor growth in castrated mice administered EPI-002 (200 mg/kg body weight) or bicalutamide (10 mg/kg body weight) daily by gavage for a total of 28 doses. Tumors were harvested 2 days after the last treatment. (B) Photographs of tumors harvested at day 28 from animals as in A. Scale bars: 10 mm. (C) Body weight change over the duration of the experiment. (D) Transcript levels of FL-AR and AR variants (V7, V567es) normalized to RPL13A using total RNA isolated from VCaP xenografts from castrated hosts treated with bicalutamide (n = 8), EPI-002 (n = 8), or DMSO control (CMC; n = 7) for 28 days. (E) Protein levels of AR and AR variants from harvested xenografts treated with EPI-002 or bicalutamide or vehicle control. Quantification of protein bands (FL-AR and AR variant), normalized to β-actin, is also shown. (F) Transcript levels of UBE2C, AKT1, CDC20, CYCLINA2, PSA, and ERG, normalized to levels of RPL13A. (G) Proliferation (Ki67) and apoptosis (caspase-3) index, measured in harvested VCaP xenografts. Data are mean ± SEM. *P < 0.05; **P < 0.01; #P < 0.001.