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"True" antiandrogens-selective non-ligand-binding pocket disruptors of androgen receptor-coactivator interactions: novel tools for prostate cancer.

Caboni L, Kinsella GK, Blanco F, Fayne D, Jagoe WN, Carr M, Williams DC, Meegan MJ, Lloyd DG - J. Med. Chem. (2012)

Bottom Line: We report the identification and characterization of a novel series of diarylhydrazides as selective disruptors of AR interaction with coactivators through application of structure and ligand-based virtual screening.Compounds demonstrate full ("true") antagonism in AR with low micromolar potency, selectivity over estrogen receptors α and β and glucocorticoid receptor, and partial antagonism of the progesterone receptor.These data provide compelling evidence for such non-LBP intervention as an alternative approach or in combination with classical PCa therapy.

View Article: PubMed Central - PubMed

Affiliation: Molecular Design Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland.

ABSTRACT
Prostate cancer (PCa) therapy typically involves administration of "classical" antiandrogens, competitive inhibitors of androgen receptor (AR) ligands, dihydrotestosterone (DHT) and testosterone (tes), for the ligand-binding pocket (LBP) in the ligand-binding domain (LBD) of AR. Prolonged LBP-targeting leads to resistance, and alternative therapies are urgently required. We report the identification and characterization of a novel series of diarylhydrazides as selective disruptors of AR interaction with coactivators through application of structure and ligand-based virtual screening. Compounds demonstrate full ("true") antagonism in AR with low micromolar potency, selectivity over estrogen receptors α and β and glucocorticoid receptor, and partial antagonism of the progesterone receptor. MDG506 (5) demonstrates low cellular toxicity in PCa models and dose responsive reduction of classical antiandrogen-induced prostate specific antigen expression. These data provide compelling evidence for such non-LBP intervention as an alternative approach or in combination with classical PCa therapy.

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Related in: MedlinePlus

Diarylhydrazides inhibit the AR recruitmentof a fluorescent-labeled D11-FxxLF peptide but do not displace a potentfluorescent ligand from the AR-LBP. (A and B) Compounds were testedin a TR-FRET assay across a concentration range from 100 μMto 45 nM in the presence of a concentration of DHT = EC80 in AR-LBD wt (A) and AR-LBD T877A (B). Data points represent themean of two independent experiments performed in triplicate. Errorbars represent the standard error of the mean (SEM) for n = 6 values. Data was fitted using log antagonist concentration vsresponse (variable slope) with GraphPad Prism 5 (see Experimental Section for details). (C) Fluorescence polarizationdata is plotted as percent maximal activity represented by AR-LBDand fluorophore complex (0% inhibition). The minimum control valuerepresents free fluorophore (Free F) in solution (100% inhibition).Error bars represent the SEM for n = 6 values.
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fig3: Diarylhydrazides inhibit the AR recruitmentof a fluorescent-labeled D11-FxxLF peptide but do not displace a potentfluorescent ligand from the AR-LBP. (A and B) Compounds were testedin a TR-FRET assay across a concentration range from 100 μMto 45 nM in the presence of a concentration of DHT = EC80 in AR-LBD wt (A) and AR-LBD T877A (B). Data points represent themean of two independent experiments performed in triplicate. Errorbars represent the standard error of the mean (SEM) for n = 6 values. Data was fitted using log antagonist concentration vsresponse (variable slope) with GraphPad Prism 5 (see Experimental Section for details). (C) Fluorescence polarizationdata is plotted as percent maximal activity represented by AR-LBDand fluorophore complex (0% inhibition). The minimum control valuerepresents free fluorophore (Free F) in solution (100% inhibition).Error bars represent the SEM for n = 6 values.

Mentions: A 12-point dose–responsecurve was determined for those compounds that inhibited coactivatorbinding in the micromolar range, acting as full AR antagonists, 3–6 (Figure 3Aand Table 1).


"True" antiandrogens-selective non-ligand-binding pocket disruptors of androgen receptor-coactivator interactions: novel tools for prostate cancer.

Caboni L, Kinsella GK, Blanco F, Fayne D, Jagoe WN, Carr M, Williams DC, Meegan MJ, Lloyd DG - J. Med. Chem. (2012)

Diarylhydrazides inhibit the AR recruitmentof a fluorescent-labeled D11-FxxLF peptide but do not displace a potentfluorescent ligand from the AR-LBP. (A and B) Compounds were testedin a TR-FRET assay across a concentration range from 100 μMto 45 nM in the presence of a concentration of DHT = EC80 in AR-LBD wt (A) and AR-LBD T877A (B). Data points represent themean of two independent experiments performed in triplicate. Errorbars represent the standard error of the mean (SEM) for n = 6 values. Data was fitted using log antagonist concentration vsresponse (variable slope) with GraphPad Prism 5 (see Experimental Section for details). (C) Fluorescence polarizationdata is plotted as percent maximal activity represented by AR-LBDand fluorophore complex (0% inhibition). The minimum control valuerepresents free fluorophore (Free F) in solution (100% inhibition).Error bars represent the SEM for n = 6 values.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3295204&req=5

fig3: Diarylhydrazides inhibit the AR recruitmentof a fluorescent-labeled D11-FxxLF peptide but do not displace a potentfluorescent ligand from the AR-LBP. (A and B) Compounds were testedin a TR-FRET assay across a concentration range from 100 μMto 45 nM in the presence of a concentration of DHT = EC80 in AR-LBD wt (A) and AR-LBD T877A (B). Data points represent themean of two independent experiments performed in triplicate. Errorbars represent the standard error of the mean (SEM) for n = 6 values. Data was fitted using log antagonist concentration vsresponse (variable slope) with GraphPad Prism 5 (see Experimental Section for details). (C) Fluorescence polarizationdata is plotted as percent maximal activity represented by AR-LBDand fluorophore complex (0% inhibition). The minimum control valuerepresents free fluorophore (Free F) in solution (100% inhibition).Error bars represent the SEM for n = 6 values.
Mentions: A 12-point dose–responsecurve was determined for those compounds that inhibited coactivatorbinding in the micromolar range, acting as full AR antagonists, 3–6 (Figure 3Aand Table 1).

Bottom Line: We report the identification and characterization of a novel series of diarylhydrazides as selective disruptors of AR interaction with coactivators through application of structure and ligand-based virtual screening.Compounds demonstrate full ("true") antagonism in AR with low micromolar potency, selectivity over estrogen receptors α and β and glucocorticoid receptor, and partial antagonism of the progesterone receptor.These data provide compelling evidence for such non-LBP intervention as an alternative approach or in combination with classical PCa therapy.

View Article: PubMed Central - PubMed

Affiliation: Molecular Design Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland.

ABSTRACT
Prostate cancer (PCa) therapy typically involves administration of "classical" antiandrogens, competitive inhibitors of androgen receptor (AR) ligands, dihydrotestosterone (DHT) and testosterone (tes), for the ligand-binding pocket (LBP) in the ligand-binding domain (LBD) of AR. Prolonged LBP-targeting leads to resistance, and alternative therapies are urgently required. We report the identification and characterization of a novel series of diarylhydrazides as selective disruptors of AR interaction with coactivators through application of structure and ligand-based virtual screening. Compounds demonstrate full ("true") antagonism in AR with low micromolar potency, selectivity over estrogen receptors α and β and glucocorticoid receptor, and partial antagonism of the progesterone receptor. MDG506 (5) demonstrates low cellular toxicity in PCa models and dose responsive reduction of classical antiandrogen-induced prostate specific antigen expression. These data provide compelling evidence for such non-LBP intervention as an alternative approach or in combination with classical PCa therapy.

Show MeSH
Related in: MedlinePlus