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Targeting the androgen receptor N-terminus via the cochaperone Bag-1L

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE89939 | GEO | 2017/08/23

SECONDARY ACCESSION(S): PRJNA354287

REPOSITORIES: GEO

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Targeting the androgen receptor N-terminus via the cochaperone Bag-1L [ChIP-Seq]

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Targeting the androgen receptor N-terminus via the cochaperone Bag-1L

Project description:Targeting the androgen receptor N-terminus via the cochaperone Bag-1L

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Development of Bag-1L as a therapeutic target in androgen receptor-dependent prostate cancer.

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Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

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Project description:All current clinically approved androgen deprivation therapies for prostate cancer (PCa) target the C-terminal ligand-binding domain (LBD) of the androgen receptor (AR), although the N-terminal domain (NTD) is the main regulator of AR activity. Targeting the AR NTD directly is a challenge because of its intrinsic disordered nature and the lack of secondary structure and clefts for drugs to bind. Here, we make use of the cochaperone BAG1L that functions through the NTD to develop alternative AR inhibitors. We show that BAG1L binds to a short alpha-helical region of the AR NTD and regulates AR dynamics and the expression of AR target genes. We further show that disruption of the BAG1L-AR NTD action by a small molecule 2-(4-fluorophenyl)-5-(trifluoromethyl)-1,3-benzothiazole (A4B17) downregulates AR target gene expression and blocks proliferation of AR-positive PCa cells. Targeting a cochaperone as a surrogate to the AR NTD is therefore key to developing novel AR antagonists.

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