Perspectives on designs of antiandrogens for prostate cancer

University of California San Francisco, Department of Biochemistry and Biophysics, San Francisco, CA941432240, USA +1 415 476 5051
Expert Opinion on Drug Discovery (Impact Factor: 3.54). 10/2007; 2(10):1341-55. DOI: 10.1517/17460441.2.10.1341
Source: PubMed


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.

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    • "Consequently antagonist-like H12 conformation/s are thought to prevent the correct surface arrangement of AF-2 for productive co-activator binding (78). The AR LBD has also been shown to feature another hydrophobic exposed groove susceptible of pharmaceutical attack called Binding Function 3 (BF-3), which has been shown to modulate coactivator recruitment via allosteric communication and it is hypothesized to be implicated in the recruitment of AR coregulatory proteins and is also an emerging non-LBP druggable site [79] [80] [81] [82] [83] [84] [85] [86] [87]. This surface is adjacent to AF-2 coactivator binding pocket and comprises residues (I672, F673, P723, G724, N727, F826, Q829, Q837, N833 and R84), belonging to H1, H3-5 and H9 [83]. "
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