Effective Targeting of the Survivin Dimerization Interface with Small-Molecule Inhibitors Article (Faculty180)

cited authors

  • Qi, Jing; Dong, Zizheng; Liu, Jianguo; Peery, Robert C; Zhang, Shaobo; Liu, Jing- Y; Zhang, Jian- T


  • 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.

publication date

  • 2016

published in

start page

  • 453

end page

  • 62


  • 76