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J Steroid Biochem Mol Biol. 2016 Jul;161:36-44. doi: 10.1016/j.jsbmb.2015.07.006. Epub 2015 Jul 18.

Recent progress in the development of protein-protein interaction inhibitors targeting androgen receptor-coactivator binding in prostate cancer.

Author information

1
Faculty of Pharmacy and Centre de recherche en endocrinologie moléculaire et oncologique et génomique humaine, Université Laval, Canada; Laboratory of Medicinal Chemistry, CHU de Québec Research Centre, G1 V 4G2, Québec, QC, Canada. Electronic address: eric.biron@pha.ulaval.ca.
2
Faculty of Pharmacy and Centre de recherche en endocrinologie moléculaire et oncologique et génomique humaine, Université Laval, Canada; Laboratory of Medicinal Chemistry, CHU de Québec Research Centre, G1 V 4G2, Québec, QC, Canada.

Abstract

The androgen receptor (AR) is a key regulator for the growth, differentiation and survival of prostate cancer cells. Identified as a primary target for the treatment of prostate cancer, many therapeutic strategies have been developed to attenuate AR signaling in prostate cancer cells. While frontline androgen-deprivation therapies targeting either the production or action of androgens usually yield favorable responses in prostate cancer patients, a significant number acquire treatment resistance. Known as the castration-resistant prostate cancer (CRPC), the treatment options are limited for this advanced stage. It has been shown that AR signaling is restored in CRPC due to many aberrant mechanisms such as AR mutations, amplification or expression of constitutively active splice-variants. Coregulator recruitment is a crucial regulatory step in AR signaling and the direct blockade of coactivator binding to AR offers the opportunity to develop therapeutic agents that would remain effective in prostate cancer cells resistant to conventional endocrine therapies. Structural analyses of the AR have identified key surfaces involved in protein-protein interaction with coregulators that have been recently used to design and develop promising AR-coactivator binding inhibitors. In this review we will discuss the design and development of small-molecule inhibitors targeting the AR-coactivator interactions for the treatment of prostate cancer.

KEYWORDS:

Androgen receptor; Coactivator binding inhibition; Coregulator recruitment; Peptidomimetics; Prostate cancer; Protein–protein interactions

PMID:
26196120
DOI:
10.1016/j.jsbmb.2015.07.006
[Indexed for MEDLINE]
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