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Title:
Peptidomimetic targeting of critical androgen receptor–coregulator interactions in prostate cancer | Nature Communications
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The growth of advanced prostate cancer depends on androgen receptor signalling, however treatment options are limited. Here we report the disruption of specific protein–protein interactions involving LXXLL motifs in androgen receptor–coregulator proteins such as PELP1 using a novel, small molecule peptidomimetic (D2). D2 is stable, non-toxic and efficiently taken up by prostate cancer cells. Importantly, D2 blocks androgen-induced nuclear uptake and genomic activity of the androgen receptor. Furthermore, D2 abrogates androgen-induced proliferation of prostate cancer cells in vitro with an IC50 of 40 nM, and inhibits tumour growth in a mouse xenograft model. D2 also disrupts androgen receptor–coregulator interactions in ex vivo cultures of primary human prostate tumours. These findings provide evidence that targeting androgen receptor–coregulator interactions using peptidomimetics may be a viable therapeutic approach for patients with advanced prostate cancer. Androgen receptor signalling plays an important role in driving prostate cancer progression. Here the authors design a peptidomimetic that blocks the interaction between the androgen receptor and its coactivator PELP1, and show that the drug slows prostate cancer cell growth in a xenograft model.
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cancer, cells, prostate, article, fig, pelp, google, scholar, cas, cell, androgen, lxxll, interaction, activity, receptor, dht, data, expression, dmso, nuclear, proliferation, treatment, lncap, dhtinduced, supplementary, nature, growth, protein, interactions, motif, shown, peptidomimetic, control, binding, proteins, experiments, performed, targeting, blocks, peptidomimetics, gene, university, tumours, blocked, analysis, including, genes, presence, effect, critical,
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nature portfolio permissions reprints privacy policy editing advertising medical research council scripps research institute nature p53-hdm2 protein-protein interaction east hanover author information authors full size image real-time nuclear localization ligand-dependent transcription factor er-coregulator pelp1/mnar c-terminal ligand-binding domain castration-resistant prostate cancer oligoamide alpha-helix mimetics affect dht-induced translocation gb/sa solvation model28 inhibiting androgen-induced activation full access developed oligo-benzamide scaffolds larger oligo-benzamide scaffolds metastatic renal-cell carcinoma phenol-red-free rpmi 1640 genome-wide microarray profiling bis-benzamide-based peptidomimetic d2 author correspondence tae-kyung lee freshly extirpated high-risk protease-mediated proteolytic degradation full-length ar activity sds–polyacrylamide gel electrophoresis ar-mediated transcriptional regulation21 leucine-rich protein-1/modulator jer-tsong hsieh & ganesh androgen-independent prostate cancer prostate cancer development dht-induced genomic activity ar-dependent mechanisms highlight hormone-refractory prostate cancer post-chemotherapy crpc patients38 dht-induced genomic function oligo-benzamide-based peptidomimetics middle panel serum-starvation conditions androgen receptor–coregulator proteins dht-mediated cell proliferation reactions including o-alkylation
Questions {❓}
- Steroid hormone receptors in prostate cancer: a hard habit to break?
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