Structure-based design, synthesis, and evaluation of conformationally constrained mimetics of the second mitochondria-derived activator of caspase that target the X-linked inhibitor of apoptosis protein/caspase-9 interaction site

J Med Chem. 2004 Aug 12;47(17):4147-50. doi: 10.1021/jm0499108.

Abstract

A successful structure-based design of conformationally constrained second mitochondria-derived activator of caspase (Smac) mimetics that target the XIAP/caspase-9 interaction site is described. The most potent Smac mimetic 12d has a Ki of 350 nM for binding to the XIAP BIR3 domain protein. 12d is found to be effective in enhancing apoptosis induced by cisplatin in PC-3 human prostate cancer cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Motifs
  • Apoptosis / drug effects*
  • Apoptosis Regulatory Proteins
  • Carrier Proteins / chemistry*
  • Caspase 9
  • Caspases / metabolism*
  • Cell Line, Tumor
  • Cyclization
  • Heterocyclic Compounds, 2-Ring / chemical synthesis*
  • Heterocyclic Compounds, 2-Ring / chemistry
  • Heterocyclic Compounds, 2-Ring / pharmacology
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Mitochondrial Proteins / chemistry*
  • Models, Molecular
  • Molecular Conformation
  • Molecular Mimicry
  • Oligopeptides / chemistry*
  • Protein Binding
  • Protein Structure, Tertiary
  • Proteins / metabolism*
  • Structure-Activity Relationship
  • X-Linked Inhibitor of Apoptosis Protein

Substances

  • Apoptosis Regulatory Proteins
  • Carrier Proteins
  • DIABLO protein, human
  • Heterocyclic Compounds, 2-Ring
  • Intracellular Signaling Peptides and Proteins
  • Mitochondrial Proteins
  • Oligopeptides
  • Proteins
  • X-Linked Inhibitor of Apoptosis Protein
  • XIAP protein, human
  • CASP9 protein, human
  • Caspase 9
  • Caspases