Discovery of Potent Antagonists of the Antiapoptotic Protein XIAP for the Treatment of Cancer

J Med Chem. 2004 Aug 26;47(18):4417-26. doi: 10.1021/jm040037k.

Abstract

Inhibitor of apoptosis (IAP) proteins are overexpressed in many cancers and have been implicated in tumor growth, pathogenesis, and resistance to chemo- or radiotherapy. On the basis of the NMR structure of a SMAC peptide complexed with the BIR3 domain of X-linked IAP (XIAP), a novel series of XIAP antagonists was discovered. The most potent compounds in this series bind to the baculovirus IAP repeat 3 (BIR3) domain of XIAP with single-digit nanomolar affinity and promote cell death in several human cancer cell lines. In a MDA-MB-231 breast cancer mouse xenograft model, these XIAP antagonists inhibited the growth of tumors. Close structural analogues that showed only weak binding to the XIAP-BIR3 domain were inactive in the cellular assays and showed only marginal in vivo activity. Our results are consistent with a mechanism in which ligands for the BIR3 domain of XIAP induce apoptosis by freeing up caspases. The present study validates the BIR3 domain of XIAP as a target and supports the use of small molecule XIAP antagonists as a potential therapy for cancers that overexpress XIAP.

MeSH terms

  • Animals
  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / pharmacology
  • Apoptosis / drug effects*
  • Apoptosis Regulatory Proteins
  • Binding Sites
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / pathology
  • Carrier Proteins / chemistry*
  • Carrier Proteins / therapeutic use
  • Caspases / drug effects
  • Cell Division / drug effects
  • Cell Line, Tumor
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Ligands
  • Mice
  • Mitochondrial Proteins / chemistry*
  • Mitochondrial Proteins / therapeutic use
  • Peptide Fragments / chemistry
  • Peptide Fragments / therapeutic use*
  • Protein Structure, Tertiary
  • Proteins / antagonists & inhibitors*
  • Structure-Activity Relationship
  • Transplantation, Heterologous
  • X-Linked Inhibitor of Apoptosis Protein

Substances

  • Antineoplastic Agents
  • Apoptosis Regulatory Proteins
  • Carrier Proteins
  • DIABLO protein, human
  • Diablo protein, mouse
  • Intracellular Signaling Peptides and Proteins
  • Ligands
  • Mitochondrial Proteins
  • Peptide Fragments
  • Proteins
  • X-Linked Inhibitor of Apoptosis Protein
  • XIAP protein, human
  • Caspases