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. 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

Andrew J Potter  1 , Stuart Ray, Louisa Gueritz, Claire L Nunns, Christopher J Bryant, Simon F Scrace, Natalia Matassova, Lisa Baker, Pawel Dokurno, David A Robinson, Allan E Surgenor, Ben Davis, James B Murray, Christine M Richardson, Jonathan D Moore
Affiliations

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

Andrew J Potter et al. Bioorg Med Chem Lett. .

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.

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