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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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 5

EPI inhibits splice variant ARv567es.

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EPI inhibits splice variant ARv567es. (A) COS-1 cells were transfected...
(A) COS-1 cells were transfected with PB-luciferase reporter and the ARv567es variant and treated with DMSO or 25 μM EPI-001 plus 1 nM R1881 for 24 hours. (B) ARR3-luciferase activity in LNCaP cells with endogenous FL-AR (left) or with both FL-AR and ARv567es (right), with or without MDV3100 (1 or 10 μM). (C) PSA(6.1kb)-luciferase activity in LNCaP cells with endogenous FL-AR (left) or with both FL-AR and ARv567es (right). Cells were treated with DMSO, 25 μM EPI-001, or 10 μM bicalutamide with or without 1 nM R1881 for 48 hours. (D) PB-luciferase activity in LNCaP cells with endogenous FL-AR (left) or with both FL-AR and ARv567es (right). Cells were treated with 25 μM EPI-001, 10 μM bicalutamide, and 5 μM MDV3100 for 1 hour prior to treatment with 1 nM R1881 for 24 hours. (E) Protein levels of FL-AR and ARv567es from samples in D, detected using AR-N20 antibody. Data are mean ± SEM (A and B) or mean ± SD (C and D). n = 3 separate experiments. *P < 0.05; **P < 0.01; #P < 0.001.