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

Abstract

<div>Abstract<p>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 <i>in silico</i> 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 <i>in silico</i> screening strategies to therapeutically target homodimeric oncogenic proteins considered undruggable. <i>Cancer Res; 76(2); 453–62. ©2016 AACR</i>.</p></div>