Promises and Challenges of Smac Mimetics as Cancer Therapeutics

Clin Cancer Res. 2015 Nov 15;21(22):5030-6. doi: 10.1158/1078-0432.CCR-15-0365.

Abstract

Inhibitor of Apoptosis (IAP) proteins block programmed cell death and are expressed at high levels in various human cancers, thus making them attractive targets for cancer drug development. Second mitochondrial activator of caspases (Smac) mimetics are small-molecule inhibitors that mimic Smac, an endogenous antagonist of IAP proteins. Preclinical studies have shown that Smac mimetics can directly trigger cancer cell death or, even more importantly, sensitize tumor cells for various cytotoxic therapies, including conventional chemotherapy, radiotherapy, or novel agents. Currently, several Smac mimetics are under evaluation in early clinical trials as monotherapy or in rational combinations (i.e., GDC-0917/CUDC-427, LCL161, AT-406/Debio1143, HGS1029, and TL32711/birinapant). This review discusses the promise as well as some challenges at the translational interface of exploiting Smac mimetics as cancer therapeutics.

Publication types

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

MeSH terms

  • Antineoplastic Agents / therapeutic use*
  • Apoptosis / drug effects*
  • Apoptosis Regulatory Proteins
  • Baculoviral IAP Repeat-Containing 3 Protein
  • Biomimetics
  • Clinical Trials as Topic
  • Humans
  • Inhibitor of Apoptosis Proteins / antagonists & inhibitors
  • Inhibitor of Apoptosis Proteins / therapeutic use
  • Intracellular Signaling Peptides and Proteins / therapeutic use*
  • Mitochondrial Proteins / therapeutic use*
  • Neoplasms / drug therapy*
  • Neoplasms / pathology
  • Neoplasms / radiotherapy
  • Ubiquitin-Protein Ligases / antagonists & inhibitors
  • Ubiquitin-Protein Ligases / therapeutic use
  • X-Linked Inhibitor of Apoptosis Protein / antagonists & inhibitors
  • X-Linked Inhibitor of Apoptosis Protein / therapeutic use

Substances

  • Antineoplastic Agents
  • Apoptosis Regulatory Proteins
  • DIABLO protein, human
  • Inhibitor of Apoptosis Proteins
  • Intracellular Signaling Peptides and Proteins
  • Mitochondrial Proteins
  • X-Linked Inhibitor of Apoptosis Protein
  • BIRC2 protein, human
  • BIRC3 protein, human
  • Baculoviral IAP Repeat-Containing 3 Protein
  • Ubiquitin-Protein Ligases