Small-molecule antagonists of apoptosis suppressor XIAP exhibit broad antitumor activity

Cancer Cell. 2004 Jan;5(1):25-35. doi: 10.1016/s1535-6108(03)00332-5.


Apoptosis resistance commonly occurs in cancers, preventing activation of Caspase family cell death proteases. XIAP is an endogenous inhibitor of Caspases overexpressed in many cancers. We developed an enzyme derepression assay, based on overcoming XIAP-mediated suppression of Caspase-3, and screened mixture-based combinatorial chemical libraries for compounds that reversed XIAP-mediated inhibition of Caspase-3, identifying a class of polyphenylureas with XIAP-inhibitory activity. These compounds, but not inactive structural analogs, stimulated increases in Caspase activity, directly induced apoptosis of many types of tumor cell lines in culture, and sensitized cancer cells to chemotherapeutic drugs. Active compounds also suppressed growth of established tumors in xenograft models in mice, while displaying little toxicity to normal tissues. These findings validate IAPs as targets for cancer drug discovery.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Apoptosis / drug effects*
  • Apoptosis Regulatory Proteins
  • Carrier Proteins / metabolism
  • Caspase 3
  • Caspases / metabolism*
  • Combinatorial Chemistry Techniques
  • Enzyme Induction / drug effects
  • Enzyme Induction / physiology
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Immunohistochemistry
  • Intracellular Signaling Peptides and Proteins
  • Membrane Glycoproteins / metabolism
  • Mice
  • Mitochondrial Proteins / metabolism
  • Models, Animal
  • Neoplasms, Experimental / drug therapy*
  • Proteins / antagonists & inhibitors*
  • Proteins / metabolism
  • TNF-Related Apoptosis-Inducing Ligand
  • Transplantation, Heterologous / pathology
  • Tumor Necrosis Factor-alpha / metabolism
  • X-Linked Inhibitor of Apoptosis Protein


  • Antineoplastic Agents
  • Apoptosis Regulatory Proteins
  • Carrier Proteins
  • DIABLO protein, human
  • Diablo protein, mouse
  • Enzyme Inhibitors
  • Intracellular Signaling Peptides and Proteins
  • Membrane Glycoproteins
  • Mitochondrial Proteins
  • Proteins
  • TNF-Related Apoptosis-Inducing Ligand
  • TNFSF10 protein, human
  • Tnfsf10 protein, mouse
  • Tumor Necrosis Factor-alpha
  • X-Linked Inhibitor of Apoptosis Protein
  • XIAP protein, human
  • CASP3 protein, human
  • Casp3 protein, mouse
  • Caspase 3
  • Caspases