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

Gelin Wang, Xiaoming Wang, Hong Yu, Shuguang Wei, Noelle Williams, Daniel L. Holmes, Randal Halfmann, Jacinth Naidoo, Lai Wang, Lin Li, She Chen, Patrick Harran, Xiaoguang Lei, Xiaodong Wang

Research output: Contribution to journalArticlepeer-review

83 Scopus citations


Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) activates apoptosis through the death receptors DR4 and DR5. Because of its superior safety profile and high tumor specificity compared to other TNF family members, recombinant soluble TRAIL and agonistic antibodies against its receptors are actively being developed for clinical cancer therapy. Here, we describe the identification and characterization of the small molecules that directly target DR5 to initiate apoptosis in human cancer cells. The activity was initially discovered through a high-throughput chemical screen for compounds that promote cell death in synergy with a small-molecule mimetic of Smac, the antagonist for inhibitor of apoptosis protein. Structure-activity relationship studies yielded a more potent analog called bioymifi, which can act as a single agent to induce DR5 clustering and aggregation, leading to apoptosis. Thus, this study identified potential lead compounds for the development of small-molecule TRAIL mimics targeting DR5 for cancer therapy.

Original languageEnglish (US)
Pages (from-to)84-89
Number of pages6
JournalNature chemical biology
Issue number2
StatePublished - Feb 2013

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology


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