期刊
JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY
卷 161, 期 -, 页码 36-44出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.jsbmb.2015.07.006
关键词
Prostate cancer; Androgen receptor; Coregulator recruitment; Protein-protein interactions; Coactivator binding inhibition; Peptidomimetics
资金
- Fonds de recherche du Quebec-Sante (FRQS)
- National Sciences and Engineering Research Council of Canada (NSERC)
- Fonds de recherche du Quebec-Nature et Technologie (FRQNT)
- Fondation de l'Universite Laval
- Centre de recherche en endocrinologie moleculaire et oncologique et genomique humaine (CREMOGH)
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. (C) 2015 Elsevier Ltd. All rights reserved.
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