title: Peptidomimetic targeting of critical androgen receptor-coregulator interactions in prostate cancer.
abstract: 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.
authors.affiliation: Department of Urology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390, USA.
authors.forename: Preethi
authors.initials: P
authors.lastname: Ravindranathan
authors.forename: Tae-Kyung
authors.initials: TK
authors.lastname: Lee
authors.forename: Lin
authors.initials: L
authors.lastname: Yang
authors.forename: Margaret M
authors.initials: MM
authors.lastname: Centenera
authors.forename: Lisa
authors.initials: L
authors.lastname: Butler
authors.forename: Wayne D
authors.initials: WD
authors.lastname: Tilley
authors.forename: Jer-Tsong
authors.initials: JT
authors.lastname: Hsieh
authors.forename: Jung-Mo
authors.initials: JM
authors.lastname: Ahn
authors.forename: Ganesh V
authors.initials: GV
authors.lastname: Raj
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D056970:Co-Repressor Proteins / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D008856:Microscopy, Fluorescence; D008958:Models, Molecular; D057786:Peptidomimetics / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011468:Prostatectomy; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D011485:Protein Binding / Q000187:drug effects; D017434:Protein Structure, Tertiary; D021381:Protein Transport / Q000187:drug effects; D011944:Receptors, Androgen / Q000737:chemistry / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: C410798:AR protein, human; D056970:Co-Repressor Proteins; C438485:PELP1 protein, human; D057786:Peptidomimetics; D011944:Receptors, Androgen; D014157:Transcription Factors