Effective targeting of the survivin dimerization interface with small-molecule inhibitors

Jing Qi, Zizheng Dong, Jianguo Liu, Robert C. Peery, Shaobo Zhang, Jing Yuan Liu, Jian Ting Zhang

Research output: Contribution to journalArticle

20 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)453-462
Number of pages10
JournalCancer Research
Volume76
Issue number2
DOIs
StatePublished - Jan 15 2016

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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