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Small-molecule activation of the TRAIL receptor DR5 in human cancer cells

Gelin Wang1, Xiaoming Wang, Hong Yu

  • 1Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas, USA. gelin.wang@utsouthwestern.edu

Nature Chemical Biology
|January 8, 2013
PubMed

Insights

Researchers identified novel small molecules that directly activate the DR5 receptor, initiating apoptosis in human cancer cells. These compounds represent potential new TRAIL mimics for cancer therapy.

Area of Science:

  • Molecular Biology
  • Cancer Therapeutics
  • Drug Discovery

Background:

  • Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) induces apoptosis via DR4 and DR5 death receptors.
  • TRAIL-based therapies offer a favorable safety profile and tumor specificity for cancer treatment.
  • Development of recombinant TRAIL and agonistic antibodies is ongoing for clinical applications.

Purpose of the Study:

  • To identify and characterize small molecules that directly target DR5 to induce apoptosis in human cancer cells.
  • To develop novel small-molecule TRAIL mimics for cancer therapy.

Main Methods:

  • High-throughput chemical screening for compounds synergistic with Smac mimetics.
  • Structure-activity relationship studies to optimize compound potency.
  • Characterization of small molecules that induce DR5 clustering and aggregation.

Main Results:

  • Discovery of small molecules that directly target and activate DR5.
  • Identification of a potent analog, bioymifi, capable of inducing apoptosis as a single agent.
  • Demonstration of bioymifi's ability to induce DR5 clustering and aggregation.

Conclusions:

  • Novel small molecules targeting DR5 have been identified.
  • Bioymifi acts as a potent single agent to induce cancer cell apoptosis via DR5.
  • These findings provide lead compounds for developing small-molecule TRAIL mimics for cancer therapy.

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