Design, synthesis, and evaluation of tricyclic, conformationally constrained small-molecule mimetics of second mitochondria-derived activator of caspases

J Med Chem. 2008 Dec 11;51(23):7352-5. doi: 10.1021/jm801146d.

Abstract

A series of tricyclic, conformationally constrained Smac mimetics have been designed, synthesized, and evaluated. The most potent compound 6 (WS-5) binds to XIAP, cIAP-1, and cIAP-2 with K(i) of 18, 1.1, and 4.2 nM, respectively. Compound 6 antagonizes XIAP in a functional assay, induces cIAP-1 degradation, inhibits cell growth with an IC(50) of 68 nM in the MDA-MB-231 cancer cell line, and effectively induces cancer cells to undergo apoptosis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Apoptosis / drug effects
  • Binding Sites
  • Biomimetic Materials / chemical synthesis*
  • Biomimetic Materials / chemistry
  • Biomimetic Materials / pharmacology*
  • Caspase Inhibitors
  • Caspases / metabolism
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Crystallography, X-Ray
  • Cyclization
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Drug Evaluation, Preclinical
  • Drug Screening Assays, Antitumor
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Inhibitor of Apoptosis Proteins / antagonists & inhibitors*
  • Inhibitor of Apoptosis Proteins / metabolism
  • Mitochondria / enzymology
  • Mitochondria / metabolism*
  • Models, Molecular
  • Molecular Conformation
  • Molecular Weight
  • Stereoisomerism
  • Structure-Activity Relationship

Substances

  • Antineoplastic Agents
  • Caspase Inhibitors
  • Enzyme Inhibitors
  • Inhibitor of Apoptosis Proteins
  • Caspases