Structure-guided Design of Alpha-Amino Acid-Derived Pin1 Inhibitors

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

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.

MeSH terms

  • Amino Acids / chemical synthesis
  • Amino Acids / chemistry*
  • Amino Acids / pharmacology
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / pharmacology
  • Benzimidazoles / chemistry
  • Binding Sites
  • Cell Line, Tumor
  • Crystallography, X-Ray
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology
  • Humans
  • Hydrogen Bonding
  • Indoles / chemistry
  • NIMA-Interacting Peptidylprolyl Isomerase
  • Peptidylprolyl Isomerase / antagonists & inhibitors*
  • Peptidylprolyl Isomerase / metabolism
  • Structure-Activity Relationship

Substances

  • Amino Acids
  • Antineoplastic Agents
  • Benzimidazoles
  • Enzyme Inhibitors
  • Indoles
  • NIMA-Interacting Peptidylprolyl Isomerase
  • indole
  • benzimidazole
  • PIN1 protein, human
  • Peptidylprolyl Isomerase