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. 2016 Sep 16;11(9):2499-505.
doi: 10.1021/acschembio.6b00182. Epub 2016 Jul 14.

EPI-001, A Compound Active Against Castration-Resistant Prostate Cancer, Targets Transactivation Unit 5 of the Androgen Receptor

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EPI-001, A Compound Active Against Castration-Resistant Prostate Cancer, Targets Transactivation Unit 5 of the Androgen Receptor

Eva De Mol et al. ACS Chem Biol. .
Free PMC article

Abstract

Castration-resistant prostate cancer is the lethal condition suffered by prostate cancer patients that become refractory to androgen deprivation therapy. EPI-001 is a recently identified compound active against this condition that modulates the activity of the androgen receptor, a nuclear receptor that is essential for disease progression. The mechanism by which this compound exerts its inhibitory activity is however not yet fully understood. Here we show, by using high resolution solution nuclear magnetic resonance spectroscopy, that EPI-001 selectively interacts with a partially folded region of the transactivation domain of the androgen receptor, known as transactivation unit 5, that is key for the ability of prostate cells to proliferate in the absence of androgens, a distinctive feature of castration-resistant prostate cancer. Our results can contribute to the development of more potent and less toxic novel androgen receptor antagonists for treating this disease.

Figures

Figure 1
Figure 1
Predicted properties of the sequence of the transactivation domain of AR a) Domain organization of AR , with an indication of the position of Zn atoms in the DBD (grey) and of dihydrotestosterone (DHT) in the LBD (blue). b) Definitions of activation function 1 (AF-1), transcription acctivation units 1 and 5 (Tau-1 and Tau-5), AF-1* and Tau-5* (the regions of sequence studied in this work) with an indication of the regions of low sequence complexity such as polyGln (Qn), polyPro (Pn), polyAla (An) and polyGly (Gn) tracts. c) Propensity to disorder of the NTD predicted by PONDR VL-XT with an indication of the functional motifs defining the core of Tau-1 and Tau-5, shaded in red and of the region of sequence studied in this work, shaded in grey. d) Positions of the motifs of the NTD of AR involved in protein protein interactions and acronyms of the binding partners (see main text for details). e) Propensity to adopt α-helical conformations predicted by Agadir , as a function of residue number, with an indication of the core of Tau-1 and Tau-5 (shaded in red) and AF-1* (shaded in grey).
Figure 2
Figure 2
Structural properties of the transactivation domain revealed by solution NMR a) 1H,15N-HSQC spectrum of AF-1*. b) Plot of the difference between the secondary Cα and Cβ chemical shifts measured for AF-1* with an indication of the regions of sequence with predicted disorder propensity (DP) lower than 50%, in grey, with predicted helical propensity (hel) higher than 10%, in blue, and involved in protein protein interactions (PPIs), in green and, at the bottom of the top panel, an indication of the nascent secondary structure identified experimentally (SS, cylinders indicate helical propensity, black rectangles indicate propensity to adopt an extended conformation). c) Plot of the secondary structure propensity of the residues of AF-1*, where SSP=1 indicates a fully formed helix and SSP=1 an extended conformation, obtained by using the algorithm SSP to extract the information on secondary structure contained in backbone (13Cα, 13Cβ, 13CO, 15N, HN) chemical shifts. d) Plot of the 15N transverse relaxation rates (R2) of the residues of AF-1* at 250 µM. The cores of Tau-1 and Tau-5 are shaded in red.
Figure 3
Figure 3
EPI-001 selectively interacts with transcription activation unit 5 of the transactivation domain of AR a) Structure of EPI-001 with an indication of the two stereogenic centres with the symbol *. b) Plot, as a function of residue number, of the change in 15N chemical shift of AF-1* caused by addition of EPI-001. c) Selected regions of the 1H,15N-HSQC spectrum of 25 µM AF-1* in the absence (blue) and in the presence (red) of 10 molar equivalents of EPI-001.
Figure 4
Figure 4
Scheme of the interaction of EPI-001 with partially folded of Tau-5.

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