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    Bioorg Med Chem Lett. 2010 Jan 15;20(2):586-90. doi: 10.1016/j.bmcl.2009.11.090. Epub 2009 Nov 22.

    Structure-guided design of alpha-amino acid-derived Pin1 inhibitors.

    Potter AJ, Ray S, Gueritz L, Nunns CL, Bryant CJ, Scrace SF, Matassova N, Baker L, Dokurno P, Robinson DA, Surgenor AE, Davis B, Murray JB, Richardson CM, Moore JD.

    Source

    Vernalis (R&D) Ltd, Granta Park, Great Abington, Cambridge CB21 6GB, United Kingdom.

    Erratum in

    • Bioorg Med Chem Lett. 2010 Aug 15;20(16):e1.

    Abstract

    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 alpha-benzimidazolyl-substituted amino acids. Examples inhibited Pin1 activity with IC(50) <100nM, 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.

    Copyright 2009 Elsevier Ltd. All rights reserved.

    PMID:
    19969456
    [PubMed - indexed for MEDLINE]

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