Development and characterization of nonpeptidic small molecule inhibitors of the XIAP/caspase-3 interaction

Chem Biol. 2003 Aug;10(8):759-67. doi: 10.1016/s1074-5521(03)00157-1.


Elevated expression of inhibitor of apoptosis protein (IAP) family members in various types of cancers is thought to provide a survival advantage to these cells. Thus, antiapoptotic functions of IAPs, and their potential as novel anticancer targets have attracted considerable interest. Among the IAPs, the X chromosome-linked inhibitor of apoptosis protein (XIAP) is regarded as the most potent suppressor of mammalian apoptosis through direct binding and inhibition of caspases. A high-throughput biochemical screen of a combinatorial chemical library led to the discovery of a novel nonpeptidic small molecule that has the ability to disrupt the XIAP/caspase-3 interaction. The activity of this nonpeptidic small molecule inhibitor of the XIAP/caspase-3 interaction has been characterized both in vitro and in cells. Molecules of this type can be used to conditionally inhibit the cellular function of XIAP and may provide insights into the development of therapeutic agents that act by modulating apoptotic pathways.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects
  • Caspase 3
  • Caspase Inhibitors*
  • Caspases / genetics
  • Caspases / metabolism
  • Cell Line
  • Combinatorial Chemistry Techniques
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • HCT116 Cells
  • Humans
  • Molecular Structure
  • Piperidines / pharmacology
  • Proteins / antagonists & inhibitors*
  • Proteins / genetics
  • Proteins / metabolism
  • Sulfonamides / pharmacology
  • X-Linked Inhibitor of Apoptosis Protein


  • Caspase Inhibitors
  • Enzyme Inhibitors
  • Piperidines
  • Proteins
  • Sulfonamides
  • TWX 024
  • X-Linked Inhibitor of Apoptosis Protein
  • XIAP protein, human
  • CASP3 protein, human
  • Caspase 3
  • Caspases