Effective Targeting of the Survivin Dimerization Interface with Small-Molecule Inhibitors

Cancer Res. 2016 Jan 15;76(2):453-62. doi: 10.1158/0008-5472.CAN-15-1874. Epub 2016 Jan 7.


Many oncoproteins are considered undruggable because they lack enzymatic activities. In this study, we present a small-molecule-based anticancer agent that acts by inhibiting dimerization of the oncoprotein survivin, thereby promoting its degradation along with spontaneous apoptosis in cancer cells. Through a combination of computational analysis of the dimerization interface and in silico screening, we identified one compound that induced proteasome-dependent survivin degradation. Analysis of a set of structural analogues led us to identify a lead compound (LQZ-7F), which was effective in blocking the survival of multiple cancer cell lines in a low micromolar concentration range. LQZ-7F induced proteasome-dependent survivin degradation, mitotic arrest, and apoptosis, and it blocked the growth of human tumors in mouse xenograft assays. In addition to providing preclinical proof of concept for a survivin-targeting anticancer agent, our work offers novel in silico screening strategies to therapeutically target homodimeric oncogenic proteins considered undruggable.

MeSH terms

  • Animals
  • Apoptosis
  • Cell Line, Tumor
  • Dimerization*
  • Disease Models, Animal
  • Humans
  • Inhibitor of Apoptosis Proteins / genetics*
  • Inhibitor of Apoptosis Proteins / metabolism*
  • Mice
  • Models, Molecular
  • Survivin
  • Xenograft Model Antitumor Assays


  • BIRC5 protein, human
  • Inhibitor of Apoptosis Proteins
  • Survivin