An androgen receptor N-terminal domain antagonist for treating prostate cancer
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
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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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 2

Stereospecificity of EPI-001 on AR transcriptional activity.

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Stereospecificity of EPI-001 on AR transcriptional activity. (A) LNCaP c...
(A) LNCaP cells were transfected with luciferase reporters and treated with 1 nM R1881 for 48 hours. Data represent percent of control (DMSO). **P < 0.01, #P < 0.001 vs. DMSO; §P < 0.05 vs. EPI-001. (B) AR NTD transactivation assay in LNCaP cells treated with indicated concentrations of EPI-001 stereoisomers prior to treatment with 50 μM forskolin or DMSO. (C) Inhibition of androgen-induced DNA synthesis in LNCaP cells by stereoisomers of EPI-001 (25 μM) or bicalutamide (10 μM) treated with 0.1 nM R1881 for 48 hours. Data represent percent S-phase cells staining positive for BrdU incorporation (bivariate flow cytometric) from a representative experiment. (D) Effects of EPI-002 on androgen-dependent proliferation of LNCaP cells treated with R1881 compared with PC3 cell viability. (E) Decrease of CRPC LNCaP tumor volume in castrated mice administered EPI-001 mixture and stereoisomers (i.v. 50 mg/kg body weight) every other day for a total of 7 doses. Bicalutamide (10 mg/kg body weight) was administered daily by oral gavage. (F) Comparison of tumor volume from treatment with single stereoisomers. (G) Percent change of tumor volume of individual animals treated with stereoisomers or bicalutamide. (H) Body weight change at day 14 versus day 0. (I) mRNA levels of full-length AR and androgen-regulated genes measured from the LNCaP xenografts. Intact, noncastrated control group (n = 3). Values were normalized to housekeeping gene RPL13A. Data are mean ± SD (A and B) or mean ± SEM (D–F, H, and I). *P < 0.05; **P < 0.01; #P < 0.001.