Potent, orally bioavailable diazabicyclic small-molecule mimetics of second mitochondria-derived activator of caspases

J Med Chem. 2008 Dec 25;51(24):8158-62. doi: 10.1021/jm801254r.

Abstract

A series of small-molecule Smac mimetics containing a diazabicyclic core structure have been designed, synthesized, and evaluated. The most potent compound (6) binds to XIAP, cIAP-1, and cIAP-2 with K(i) values of 8.4, 1.5, and 4.2 nM, respectively, directly antagonizes XIAP in a cell-free functional assay and induces cIAP-1 degradation in cancer cells. It inhibits cell growth with an IC(50) value of 31 nM, effectively induces apoptosis in the MDA-MB-231 cancer cell line, and has a good oral bioavailability.

Publication types

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

MeSH terms

  • Administration, Oral
  • Animals
  • Baculoviral IAP Repeat-Containing 3 Protein
  • Caspase Inhibitors*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Chemistry, Pharmaceutical / methods*
  • Drug Design
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Inhibitor of Apoptosis Proteins / chemistry
  • Inhibitory Concentration 50
  • Mitochondria / enzymology
  • Mitochondria / metabolism*
  • Rats
  • Ubiquitin-Protein Ligases
  • X-Linked Inhibitor of Apoptosis Protein / chemistry

Substances

  • Caspase Inhibitors
  • Enzyme Inhibitors
  • Inhibitor of Apoptosis Proteins
  • X-Linked Inhibitor of Apoptosis Protein
  • XIAP protein, human
  • BIRC3 protein, human
  • Baculoviral IAP Repeat-Containing 3 Protein
  • Ubiquitin-Protein Ligases