کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
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1375357 | 981937 | 2010 | 5 صفحه PDF | دانلود رایگان |
The peptidyl prolyl cis/trans isomerase Pin1 is a promising molecular target for anti-cancer therapeutics. Here we report the structure-guided evolution of an indole 2-carboxylic acid fragment hit into a series of α-benzimidazolyl-substituted amino acids. Examples inhibited Pin1 activity with IC50 <100 nM, but were inactive on cells. Replacement of the benzimidazole ring with a naphthyl group resulted in a 10–50-fold loss in ligand potency, but these examples downregulated biomarkers of Pin1 activity and blocked proliferation of PC3 cells.
An indole 2-carboxylic acid fragment was evolved into a series of potent (<200 nM) α-benzimidazolyl-substituted amino acid inhibitors of the Pin1 PPIase via structure-based drug design.Figure optionsDownload as PowerPoint slide
Journal: Bioorganic & Medicinal Chemistry Letters - Volume 20, Issue 2, 15 January 2010, Pages 586–590