Targeting IAP proteins for therapeutic intervention in cancer

Nat Rev Drug Discov. 2012 Feb 1;11(2):109-24. doi: 10.1038/nrd3627.

Abstract

Evasion of apoptosis is one of the crucial acquired capabilities used by cancer cells to fend off anticancer therapies. Inhibitor of apoptosis (IAP) proteins exert a range of biological activities that promote cancer cell survival and proliferation. X chromosome-linked IAP is a direct inhibitor of caspases - pro-apoptotic executioner proteases - whereas cellular IAP proteins block the assembly of pro-apoptotic protein signalling complexes and mediate the expression of anti-apoptotic molecules. Furthermore, mutations, amplifications and chromosomal translocations of IAP genes are associated with various malignancies. Among the therapeutic strategies that have been designed to target IAP proteins, the most widely used approach is based on mimicking the IAP-binding motif of second mitochondria-derived activator of caspase (SMAC), which functions as an endogenous IAP antagonist. Alternative strategies include transcriptional repression and the use of antisense oligonucleotides. This Review provides an update on IAP protein biology as well as current and future perspectives on targeting IAP proteins for therapeutic intervention in human malignancies.

Publication types

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

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use*
  • Apoptosis / drug effects
  • Apoptosis / physiology
  • Cell Death / drug effects
  • Cell Death / physiology
  • Drug Therapy, Combination
  • Humans
  • Inhibitor of Apoptosis Proteins / antagonists & inhibitors*
  • Inhibitor of Apoptosis Proteins / drug effects
  • Inhibitor of Apoptosis Proteins / physiology
  • Neoplasms / drug therapy*
  • Oligodeoxyribonucleotides, Antisense / pharmacology
  • Oligodeoxyribonucleotides, Antisense / therapeutic use
  • Signal Transduction / drug effects
  • Signal Transduction / physiology
  • X-Linked Inhibitor of Apoptosis Protein / drug effects
  • X-Linked Inhibitor of Apoptosis Protein / physiology

Substances

  • Antineoplastic Agents
  • Inhibitor of Apoptosis Proteins
  • Oligodeoxyribonucleotides, Antisense
  • X-Linked Inhibitor of Apoptosis Protein