Perspectives on designs of antiandrogens for prostate cancer.
ABSTRACT The androgen receptor (AR) regulates gene transcription in many tissues and is profoundly important in prostate cancer. Antiandrogens compete with the natural hormone and are front line therapeutics to treat prostate cancer. However, antiandrogens frequently become ineffective after prolonged treatment because of development of tumor resistance. This paper reviews design principles for new generations of antiandrogens: super antagonists and surface allosteric modulators. Super antiandrogens are compounds with higher binding affinity than natural agonists and that contain precisely engineered hydrophobic groups that disrupt AR function. AR surface is also an attractive alternative target. Surface inhibitors are small molecules that directly block the receptor-co-activator interface, preventing co-activator recruitment. The challenges to designing these compounds are significant but so is the potential for treatment of the disease.
Full-textDOI: · Available from: Eva Estebanez-Perpiña, Apr 17, 2015
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Article: Perspectives on designs of antiandrogens for prostate cancer.
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ABSTRACT: We report the synthesis and a study of the structure activity relationships of a new series of diarylhydrazides as potential selective non-Ligand Binding Pocket Androgen Receptor antagonists. Their biological activity as antiandrogens in the context of the development of treatments for castration resistant prostate cancer was evaluated using in vitro using Time Resolved Fluorescence Resonance Energy Transfer and Fluorescence Polarisation on target assays. Additionally, a theoretical study combining docking and molecular dynamics methods was performed to provide insight to their mechanism of action as a basis for further lead optimisation studies.Journal of Chemical Information and Modeling 07/2013; 53(8). DOI:10.1021/ci400189m · 4.07 Impact Factor
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ABSTRACT: The traditional structural view of allostery defines this key regulatory mechanism as the ability of one conformational event (allosteric site) to initiate another in a separate location (active site). In recent years computational simulations conducted to understand how this phenomenon occurs in nuclear receptors (NRs) has gained significant traction. These results have yield insights into allosteric changes and communication mechanisms that underpin ligand binding, coactivator binding site formation, post-translational modifications, and oncogenic mutations. Moreover, substantial efforts have been made in understanding the dynamic processes involved in ligand binding and coregulator recruitment to different NR conformations in order to predict cell/tissue-selective pharmacological outcomes of drugs. They also have improved the accuracy of in silico screening protocols so that nowadays they are becoming part of optimisation protocols for novel therapeutics. Here we summarise the important contributions that computational simulations have made towards understanding the structure/function relationship of NRs and how these can be exploited for rational drug design.Molecular and Cellular Endocrinology 06/2014; DOI:10.1016/j.mce.2014.05.017 · 4.24 Impact Factor
Androgen Receptors: Structural Biology, Genetics and Molecular Defects., 2014 edited by Silvia Socorro, 01/2014: chapter Structural and Functional Analysis of the Androgen Receptor in Disease: pages 53-81; Nova., ISBN: 978-1-62948-693-2